The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024)
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.742C>T (p.Arg248Trp)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.742C>T (p.Arg248Trp)
Variation ID: 12347 Accession: VCV000012347.69
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674221 (GRCh38) [ NCBI UCSC ] 17: 7577539 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jan 13, 2025 Aug 5, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.742C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg248Trp missense NM_000546.5(TP53):c.742C>T NM_001126112.3:c.742C>T NP_001119584.1:p.Arg248Trp missense NM_001126113.3:c.742C>T NP_001119585.1:p.Arg248Trp missense NM_001126114.3:c.742C>T NP_001119586.1:p.Arg248Trp missense NM_001126115.2:c.346C>T NP_001119587.1:p.Arg116Trp missense NM_001126116.2:c.346C>T NP_001119588.1:p.Arg116Trp missense NM_001126117.2:c.346C>T NP_001119589.1:p.Arg116Trp missense NM_001126118.2:c.625C>T NP_001119590.1:p.Arg209Trp missense NM_001276695.3:c.625C>T NP_001263624.1:p.Arg209Trp missense NM_001276696.3:c.625C>T NP_001263625.1:p.Arg209Trp missense NM_001276697.3:c.265C>T NP_001263626.1:p.Arg89Trp missense NM_001276698.3:c.265C>T NP_001263627.1:p.Arg89Trp missense NM_001276699.3:c.265C>T NP_001263628.1:p.Arg89Trp missense NM_001276760.3:c.625C>T NP_001263689.1:p.Arg209Trp missense NM_001276761.3:c.625C>T NP_001263690.1:p.Arg209Trp missense NC_000017.11:g.7674221G>A NC_000017.10:g.7577539G>A NG_017013.2:g.18330C>T LRG_321:g.18330C>T LRG_321t1:c.742C>T LRG_321p1:p.Arg248Trp LRG_321t3:c.742C>T LRG_321p3:p.Arg248Trp P04637:p.Arg248Trp - Protein change
- R248W, R116W, R209W, R89W
- Other names
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p.R248W:CGG>TGG
- Canonical SPDI
- NC_000017.11:7674220:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3409 | 3509 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV000013140.37 | |
| Pathogenic (6) |
reviewed by expert panel
|
Aug 5, 2024 | RCV000168242.30 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2023 | RCV000115735.17 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2022 | RCV000213057.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000735293.6 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Mar 19, 2021 | RCV000785485.7 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 22, 2020 | RCV001271100.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 30, 2019 | RCV001255674.5 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Oct 30, 2020 | RCV001374442.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 25, 2023 | RCV003318332.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 10, 2022 | RCV003105772.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 16, 2023 | RCV003460463.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162243.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2021 | RCV003149569.5 | |
|
TP53-related disorder
|
Pathogenic (2) |
no assertion criteria provided
|
Oct 1, 2024 | RCV004745154.2 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Aug 05, 2024)
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reviewed by expert panel
Method: curation
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001142555.2 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024 |
Comment:
The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant … (more)
The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024) (less)
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Pathogenic
(Jan 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204074.6
First in ClinVar: Jan 31, 2015 Last updated: Jul 06, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 7
|
|
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Pathogenic
(May 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149644.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti … (more)
Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929) (less)
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Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218912.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000212766.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at … (more)
The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in many individuals and families from various ethnicities affected with Li-Fraumeni syndrome-associated cancers (Malkin D et al. Science. 1990 Nov 30;250(4985):1233-8; Bang YJ et al. J. Korean Med. Sci. 1995 Jun;10:205-10; Alsner J et al. Clin Cancer Res. 2000 Oct;6(10):3923-31; Andrade RC et al. Pediatr Blood Cancer. 2013 Sep 13; Rieber J et al. Genes Chromosomes Cancer. 2009 Jul; 48(7):558-68; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This mutation was also reported in an individual diagnosed with bilateral breast cancer at ages 29 and 34; in vitro studies showed significantly reduced induction levels of TP53 target genes in LFS lymphocytes that had been exposed to DNA damage resulting in greatly reduced cellular response to DNA damage (Zerdoumi Y et al. Hum Mutat. 2013 Mar;34(3):453-61). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In another study, a functional protein microarray indicated that TP53 polypeptide with p.R248W alteration exhibited less than 40% DNA binding activity compared to wild type protein (Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the tongue
Acute myeloid leukemia Cognitive impairment Pancytopenia Pectus excavatum Short stature Webbed neck
Affected status: yes
Allele origin:
germline
|
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854446.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: male
Ethnicity/Population group: Hispanic
|
|
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Pathogenic
(Oct 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469327.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype … (more)
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed. (less)
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Pathogenic
(Feb 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV002030213.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839113.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
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Pathogenic
(Jan 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002525951.2
First in ClinVar: Jun 18, 2022 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Jul 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488942.2
First in ClinVar: May 29, 2016 Last updated: Dec 24, 2022 |
|
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Pathogenic
(Apr 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807904.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting
Number of individuals with the variant: 1
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
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Pathogenic
(Sep 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003837775.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
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Pathogenic
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844260.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: TP53 c.742C>T (p.Arg248Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of … (more)
Variant summary: TP53 c.742C>T (p.Arg248Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.742C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome or other types of cancer. These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abrogation of Tp53 tumor suppressor activity (Fregourg_1992, Zerdoumi_2012). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003932859.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347) with 52 entries, all of which classify this variant as pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic TP53 gene cause Li-Fraumeni syndrome. (less)
Zygosity: Single Heterozygote
Age: 20-29 years
Sex: female
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|
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Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004017842.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 20522432]. Functional studies … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 20522432]. Functional studies indicate this variant impacts protein function [PMID: 17417627, 14743206, 9150393, 8062826]. (less)
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Pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244617.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PS4, PS2
|
|
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Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV002053464.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Feb 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004823768.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
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Pathogenic
(Nov 16, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206227.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Sep 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Accession: SCV005407748.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
c.742C>T, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 248, p.(Arg248Trp). It … (more)
c.742C>T, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 248, p.(Arg248Trp). It is located in a mutational hotspot (PM1). This variant is found in 1/236940 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.54) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 8 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 20522432, 1978757, 9825943, 8527048) (PS4). It has been reported in ClinVar (19x as pathogenic, 27x as likely pathogenic, 1x VUS) variant and LOVD (5x as pathogenic variant, 1x as NA). Based on the currently available information, c.742C>T is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. (less)
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Pathogenic
(Jul 15, 1992)
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no assertion criteria provided
Method: literature only
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LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000033387.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 13, 2025 |
Comment on evidence:
Malkin et al. (1990) demonstrated that alterations of the TP53 gene occur not only as somatic mutations in human cancers, but also as germline mutations … (more)
Malkin et al. (1990) demonstrated that alterations of the TP53 gene occur not only as somatic mutations in human cancers, but also as germline mutations in some cancer-prone families. In 2 families with Li-Fraumeni syndrome-1 (151623), they identified a C-to-T mutation at the first nucleotide of codon 248, changing arginine to tryptophan (R248W). Loss of the wildtype allele was found in the tumor in some cases. By transfection of the R248W mutant into malignant cells, Frebourg et al. (1992) demonstrated loss of tumor suppressor activity. (less)
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Likely pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000924057.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Observation 1: Observation 2: |
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Pathogenic
(Apr 30, 2019)
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no assertion criteria provided
Method: research
|
Lip and oral cavity carcinoma
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432239.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Dec 22, 2020)
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no assertion criteria provided
Method: clinical testing
|
Choroid plexus carcinoma
Affected status: yes
Allele origin:
germline
|
Michigan Center for Translational Pathology, University of Michigan
Accession: SCV001451929.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
Age: 0-9 years
Sex: male
Ethnicity/Population group: Caucasian
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Uncertain significance
(Oct 30, 2020)
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no assertion criteria provided
Method: research
|
Gallbladder cancer
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001571405.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
|
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Pathogenic
(Mar 19, 2021)
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no assertion criteria provided
Method: clinical testing
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Ovarian cancer
Affected status: no
Allele origin:
somatic
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738478.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
|
|
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739798.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905841.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
|
|
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956921.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758166.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
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Pathogenic
(May 10, 2022)
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no assertion criteria provided
Method: clinical testing
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Congenital fibrosarcoma
Affected status: yes
Allele origin:
somatic
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003762123.1
First in ClinVar: Feb 13, 2023 Last updated: Feb 13, 2023 |
|
|
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Pathogenic
(Jul 25, 2023)
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no assertion criteria provided
Method: clinical testing
|
Malignant lymphoma, large B-cell, diffuse
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Wasik Lab, Fox Chase Cancer Center
Accession: SCV004020303.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial … (more)
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TP53 tumor suppressor dysregulation is associated with partial or no response to CHOP-based chemotherapy (Young et al. 2007; Xu-Monette et al. 2012). TP53 mutations frequently involve the DNA binding domain, exons 5-8, impairing TP53 mediated transcriptional transactivation (Miao et al. 2019). TP53 R248W was detected in this tumor at presentation and recurrence, and is predicted to cause structural defects in the region responsible for DNA binding. Genomic DNA copy number assays indicated the normal TP53 allele was lost at relapse. TP53 mutation is uncommon in the MYD88 cluster of DLBCL but when present, it confers an extremely poor prognosis (Lacy et al. 2020). (less)
Indication for testing: DLBCL
Zygosity: Single Heterozygote
Age: 50-59 years
Sex: female
Comment on evidence:
Peripheral blood containing DLBCL collected for sequencing at initial diagnosis August 2018. Tumor tissue sequenced at recurrence September 2019.
Testing laboratory: Genoptix
Date variant was reported to submitter: 2019-10-10
Testing laboratory interpretation: Pathogenic
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|
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Pathogenic
(Aug 09, 2024)
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no assertion criteria provided
Method: clinical testing
|
TP53-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005345291.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TP53 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Trp. This variant has been reported in multiple individuals with Li-Fraumeni syndrome … (more)
The TP53 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Trp. This variant has been reported in multiple individuals with Li-Fraumeni syndrome and breast cancer and has been observed to segregate with disease in related individuals (Malkin et al. 1990. PubMed ID: 1978757; Zerdoumi et al. 2013. PubMed ID: 23172776; Brugières et al. 1993. PubMed ID: 8425176; Varley et al. 1997. PubMed ID: 9242456). This variant is in a codon (p.Arg248) that is an established mutational hotspot (Olivier et al. 2010. PMID: 20182602) and functional studies demonstrate that this variant impacts protein function (Kato et al. 2003. PubMed ID: 12826609; Giacomelli et al. 2018. PubMed ID: 30224644; Kotler et al. 2018. PubMed ID: 29979965). An alternate nucleotide change affecting the same amino acid (p.Arg248Gln), has been reported in individuals with TP53-related conditions (Varley et al. 1997. PubMed ID: 9242456). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12347/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 01, 2024)
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no assertion criteria provided
Method: clinical testing
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TP53-related disorder
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV005419158.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
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Comment:
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in many individuals and families from various ethnicities affected with Li-Fraumeni syndrome-associated cancers (Malkin D et al. Science. 1990 Nov 30;250(4985):1233-8; Bang YJ et al. J. Korean Med. Sci. 1995 Jun;10:205-10; Alsner J et al. Clin Cancer Res. 2000 Oct;6(10):3923-31; Andrade RC et al. Pediatr Blood Cancer. 2013 Sep 13; Rieber J et al. Genes Chromosomes Cancer. 2009 Jul; 48(7):558-68; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This mutation was also reported in an individual diagnosed with bilateral breast cancer at ages 29 and 34; in vitro studies showed significantly reduced induction levels of TP53 target genes in LFS lymphocytes that had been exposed to DNA damage resulting in greatly reduced cellular response to DNA damage (Zerdoumi Y et al. Hum Mutat. 2013 Mar;34(3):453-61). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In another study, a functional protein microarray indicated that TP53 polypeptide with p.R248W alteration exhibited less than 40% DNA binding activity compared to wild type protein (Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting
Comment:
Variant summary: TP53 c.742C>T (p.Arg248Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.742C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome or other types of cancer. These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abrogation of Tp53 tumor suppressor activity (Fregourg_1992, Zerdoumi_2012). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347) with 52 entries, all of which classify this variant as pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic TP53 gene cause Li-Fraumeni syndrome.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 20522432]. Functional studies indicate this variant impacts protein function [PMID: 17417627, 14743206, 9150393, 8062826].
Comment:
PS3, PS4, PS2
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
c.742C>T, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 248, p.(Arg248Trp). It is located in a mutational hotspot (PM1). This variant is found in 1/236940 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.54) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 8 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 20522432, 1978757, 9825943, 8527048) (PS4). It has been reported in ClinVar (19x as pathogenic, 27x as likely pathogenic, 1x VUS) variant and LOVD (5x as pathogenic variant, 1x as NA). Based on the currently available information, c.742C>T is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TP53 tumor suppressor dysregulation is associated with partial or no response to CHOP-based chemotherapy (Young et al. 2007; Xu-Monette et al. 2012). TP53 mutations frequently involve the DNA binding domain, exons 5-8, impairing TP53 mediated transcriptional transactivation (Miao et al. 2019). TP53 R248W was detected in this tumor at presentation and recurrence, and is predicted to cause structural defects in the region responsible for DNA binding. Genomic DNA copy number assays indicated the normal TP53 allele was lost at relapse. TP53 mutation is uncommon in the MYD88 cluster of DLBCL but when present, it confers an extremely poor prognosis (Lacy et al. 2020).
Comment:
The TP53 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Trp. This variant has been reported in multiple individuals with Li-Fraumeni syndrome and breast cancer and has been observed to segregate with disease in related individuals (Malkin et al. 1990. PubMed ID: 1978757; Zerdoumi et al. 2013. PubMed ID: 23172776; Brugières et al. 1993. PubMed ID: 8425176; Varley et al. 1997. PubMed ID: 9242456). This variant is in a codon (p.Arg248) that is an established mutational hotspot (Olivier et al. 2010. PMID: 20182602) and functional studies demonstrate that this variant impacts protein function (Kato et al. 2003. PubMed ID: 12826609; Giacomelli et al. 2018. PubMed ID: 30224644; Kotler et al. 2018. PubMed ID: 29979965). An alternate nucleotide change affecting the same amino acid (p.Arg248Gln), has been reported in individuals with TP53-related conditions (Varley et al. 1997. PubMed ID: 9242456). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12347/). This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024)
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in many individuals and families from various ethnicities affected with Li-Fraumeni syndrome-associated cancers (Malkin D et al. Science. 1990 Nov 30;250(4985):1233-8; Bang YJ et al. J. Korean Med. Sci. 1995 Jun;10:205-10; Alsner J et al. Clin Cancer Res. 2000 Oct;6(10):3923-31; Andrade RC et al. Pediatr Blood Cancer. 2013 Sep 13; Rieber J et al. Genes Chromosomes Cancer. 2009 Jul; 48(7):558-68; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This mutation was also reported in an individual diagnosed with bilateral breast cancer at ages 29 and 34; in vitro studies showed significantly reduced induction levels of TP53 target genes in LFS lymphocytes that had been exposed to DNA damage resulting in greatly reduced cellular response to DNA damage (Zerdoumi Y et al. Hum Mutat. 2013 Mar;34(3):453-61). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In another study, a functional protein microarray indicated that TP53 polypeptide with p.R248W alteration exhibited less than 40% DNA binding activity compared to wild type protein (Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting
Comment:
Variant summary: TP53 c.742C>T (p.Arg248Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.742C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome or other types of cancer. These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abrogation of Tp53 tumor suppressor activity (Fregourg_1992, Zerdoumi_2012). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347) with 52 entries, all of which classify this variant as pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic TP53 gene cause Li-Fraumeni syndrome.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 20522432]. Functional studies indicate this variant impacts protein function [PMID: 17417627, 14743206, 9150393, 8062826].
Comment:
PS3, PS4, PS2
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
c.742C>T, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 248, p.(Arg248Trp). It is located in a mutational hotspot (PM1). This variant is found in 1/236940 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.54) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 8 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 20522432, 1978757, 9825943, 8527048) (PS4). It has been reported in ClinVar (19x as pathogenic, 27x as likely pathogenic, 1x VUS) variant and LOVD (5x as pathogenic variant, 1x as NA). Based on the currently available information, c.742C>T is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TP53 tumor suppressor dysregulation is associated with partial or no response to CHOP-based chemotherapy (Young et al. 2007; Xu-Monette et al. 2012). TP53 mutations frequently involve the DNA binding domain, exons 5-8, impairing TP53 mediated transcriptional transactivation (Miao et al. 2019). TP53 R248W was detected in this tumor at presentation and recurrence, and is predicted to cause structural defects in the region responsible for DNA binding. Genomic DNA copy number assays indicated the normal TP53 allele was lost at relapse. TP53 mutation is uncommon in the MYD88 cluster of DLBCL but when present, it confers an extremely poor prognosis (Lacy et al. 2020).
Comment:
The TP53 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Trp. This variant has been reported in multiple individuals with Li-Fraumeni syndrome and breast cancer and has been observed to segregate with disease in related individuals (Malkin et al. 1990. PubMed ID: 1978757; Zerdoumi et al. 2013. PubMed ID: 23172776; Brugières et al. 1993. PubMed ID: 8425176; Varley et al. 1997. PubMed ID: 9242456). This variant is in a codon (p.Arg248) that is an established mutational hotspot (Olivier et al. 2010. PMID: 20182602) and functional studies demonstrate that this variant impacts protein function (Kato et al. 2003. PubMed ID: 12826609; Giacomelli et al. 2018. PubMed ID: 30224644; Kotler et al. 2018. PubMed ID: 29979965). An alternate nucleotide change affecting the same amino acid (p.Arg248Gln), has been reported in individuals with TP53-related conditions (Varley et al. 1997. PubMed ID: 9242456). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12347/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. | Fortuno C | Human mutation | 2021 | PMID: 33300245 |
| Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report. | Lacy SE | Blood | 2020 | PMID: 32187361 |
| Genetic alterations and their clinical implications in DLBCL. | Miao Y | Nature reviews. Clinical oncology | 2019 | PMID: 31127191 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| Constitutional mosaicism of a de novo TP53 mutation in a patient with bilateral choroid plexus carcinoma. | Trubicka J | Cancer genetics | 2017 | PMID: 29025599 |
| Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
| Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. | Zerdoumi Y | Human molecular genetics | 2017 | PMID: 28472496 |
| Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. | Zerdoumi Y | Human molecular genetics | 2017 | PMID: 28369373 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 27374712 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. | Meric-Bernstam F | Annals of oncology : official journal of the European Society for Medical Oncology | 2016 | PMID: 26787237 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
| TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
| TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
| Germline TP53 mutational spectrum in French Canadians with breast cancer. | Arcand SL | BMC medical genetics | 2015 | PMID: 25925845 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. | Kool M | Cancer cell | 2014 | PMID: 24651015 |
| Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity. | Xu J | Cell death & disease | 2014 | PMID: 24603336 |
| Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. | Xu J | Scientific reports | 2014 | PMID: 24573247 |
| Association of TP53 polymorphisms on the risk of Wilms tumor. | Andrade RC | Pediatric blood & cancer | 2014 | PMID: 24038938 |
| Clinical response to a lapatinib-based therapy for a Li-Fraumeni syndrome patient with a novel HER2V659E mutation. | Serra V | Cancer discovery | 2013 | PMID: 23950206 |
| A young woman with bilateral breast cancer: identifying a genetic cause and implications for management. | de Bruin MA | Journal of the National Comprehensive Cancer Network : JNCCN | 2013 | PMID: 23667202 |
| Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
| Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. | Zerdoumi Y | Human mutation | 2013 | PMID: 23172776 |
| Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. | Xu-Monette ZY | Blood | 2012 | PMID: 22955915 |
| A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
| Mutant p53: one name, many proteins. | Freed-Pastor WA | Genes & development | 2012 | PMID: 22713868 |
| Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. | Rausch T | Cell | 2012 | PMID: 22265402 |
| TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
| Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. | Villani A | The Lancet. Oncology | 2011 | PMID: 21601526 |
| TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. | Heymann S | Radiation oncology (London, England) | 2010 | PMID: 21059199 |
| TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. | Ruijs MW | Journal of medical genetics | 2010 | PMID: 20522432 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| TP53 mutations in human cancers: origins, consequences, and clinical use. | Olivier M | Cold Spring Harbor perspectives in biology | 2010 | PMID: 20182602 |
| Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
| p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells. | Ikezoe T | International journal of hematology | 2010 | PMID: 20013323 |
| Novel oncogene amplifications in tumors from a family with Li-Fraumeni syndrome. | Rieber J | Genes, chromosomes & cancer | 2009 | PMID: 19378321 |
| Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation. | Rossbach HC | Pediatric blood & cancer | 2008 | PMID: 17427234 |
| Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma. | Young KH | Blood | 2007 | PMID: 17881637 |
| Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
| p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. | Song H | Nature cell biology | 2007 | PMID: 17417627 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. | Willis A | Oncogene | 2004 | PMID: 14743206 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients. | Alsner J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2000 | PMID: 11051239 |
| Germline mutations of the p53 gene in children with malignant solid tumors. | Ayan I | Journal of experimental & clinical cancer research : CR | 1998 | PMID: 10089074 |
| Astrocytomas and choroid plexus tumors in two families with identical p53 germline mutations. | Vital A | Journal of neuropathology and experimental neurology | 1998 | PMID: 9825943 |
| Simultaneous adrenocortical carcinoma and ganglioneuroblastoma in a child with Turner syndrome and germline p53 mutation. | Pivnick EK | Journal of medical genetics | 1998 | PMID: 9598730 |
| Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. | Varley JM | Cancer research | 1997 | PMID: 9242456 |
| Two functional assays employed to detect an unusual mutation in the oligomerisation domain of p53 in a Li-Fraumeni like family. | Lomax ME | Oncogene | 1997 | PMID: 9150393 |
| The first documentation of Li-Fraumeni syndrome in Korea. | Bang YJ | Journal of Korean medical science | 1995 | PMID: 8527048 |
| Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. | Ory K | The EMBO journal | 1994 | PMID: 8062826 |
| Screening for germ line p53 mutations in children with malignant tumors and a family history of cancer. | Brugières L | Cancer research | 1993 | PMID: 8425176 |
| Gain of function mutations in p53. | Dittmer D | Nature genetics | 1993 | PMID: 8099841 |
| Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. | Frebourg T | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1631137 |
| Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. | Malkin D | Science (New York, N.Y.) | 1990 | PMID: 1978757 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/55c3283e-f0f6-4e18-b837-99a275ea7d90 | - | - | - | - |
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Conditions - Somatic
| Tumor type
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The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
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The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
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The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
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The most recent date that a submitter evaluated this variant for the tumor type. |
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Oncogenic
criteria provided, single submitter
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Jul 31, 2024 | RCV000438698.7 |
Submissions - Somatic
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Oncogenicity
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The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
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The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Oncogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm
Affected status: unknown
Allele origin:
somatic
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094410.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
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Comment:
The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024)
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in many individuals and families from various ethnicities affected with Li-Fraumeni syndrome-associated cancers (Malkin D et al. Science. 1990 Nov 30;250(4985):1233-8; Bang YJ et al. J. Korean Med. Sci. 1995 Jun;10:205-10; Alsner J et al. Clin Cancer Res. 2000 Oct;6(10):3923-31; Andrade RC et al. Pediatr Blood Cancer. 2013 Sep 13; Rieber J et al. Genes Chromosomes Cancer. 2009 Jul; 48(7):558-68; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This mutation was also reported in an individual diagnosed with bilateral breast cancer at ages 29 and 34; in vitro studies showed significantly reduced induction levels of TP53 target genes in LFS lymphocytes that had been exposed to DNA damage resulting in greatly reduced cellular response to DNA damage (Zerdoumi Y et al. Hum Mutat. 2013 Mar;34(3):453-61). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In another study, a functional protein microarray indicated that TP53 polypeptide with p.R248W alteration exhibited less than 40% DNA binding activity compared to wild type protein (Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting
Comment:
Variant summary: TP53 c.742C>T (p.Arg248Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.742C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome or other types of cancer. These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abrogation of Tp53 tumor suppressor activity (Fregourg_1992, Zerdoumi_2012). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347) with 52 entries, all of which classify this variant as pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic TP53 gene cause Li-Fraumeni syndrome.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 20522432]. Functional studies indicate this variant impacts protein function [PMID: 17417627, 14743206, 9150393, 8062826].
Comment:
PS3, PS4, PS2
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
c.742C>T, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 248, p.(Arg248Trp). It is located in a mutational hotspot (PM1). This variant is found in 1/236940 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.54) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 8 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 20522432, 1978757, 9825943, 8527048) (PS4). It has been reported in ClinVar (19x as pathogenic, 27x as likely pathogenic, 1x VUS) variant and LOVD (5x as pathogenic variant, 1x as NA). Based on the currently available information, c.742C>T is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TP53 tumor suppressor dysregulation is associated with partial or no response to CHOP-based chemotherapy (Young et al. 2007; Xu-Monette et al. 2012). TP53 mutations frequently involve the DNA binding domain, exons 5-8, impairing TP53 mediated transcriptional transactivation (Miao et al. 2019). TP53 R248W was detected in this tumor at presentation and recurrence, and is predicted to cause structural defects in the region responsible for DNA binding. Genomic DNA copy number assays indicated the normal TP53 allele was lost at relapse. TP53 mutation is uncommon in the MYD88 cluster of DLBCL but when present, it confers an extremely poor prognosis (Lacy et al. 2020).
Comment:
The TP53 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Trp. This variant has been reported in multiple individuals with Li-Fraumeni syndrome and breast cancer and has been observed to segregate with disease in related individuals (Malkin et al. 1990. PubMed ID: 1978757; Zerdoumi et al. 2013. PubMed ID: 23172776; Brugières et al. 1993. PubMed ID: 8425176; Varley et al. 1997. PubMed ID: 9242456). This variant is in a codon (p.Arg248) that is an established mutational hotspot (Olivier et al. 2010. PMID: 20182602) and functional studies demonstrate that this variant impacts protein function (Kato et al. 2003. PubMed ID: 12826609; Giacomelli et al. 2018. PubMed ID: 30224644; Kotler et al. 2018. PubMed ID: 29979965). An alternate nucleotide change affecting the same amino acid (p.Arg248Gln), has been reported in individuals with TP53-related conditions (Varley et al. 1997. PubMed ID: 9242456). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12347/). This variant is interpreted as pathogenic.
Citations for somatic classification of this variant
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Text-mined citations for rs121912651 ...
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Record last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.