This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_004064.5(CDKN1B):c.206C>T (p.Pro69Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline 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.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(4)
Likely pathogenic(1); Uncertain significance(4)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004064.5(CDKN1B):c.206C>T (p.Pro69Leu)
Variation ID: 183393 Accession: VCV000183393.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.1 12: 12718045 (GRCh38) [ NCBI UCSC ] 12: 12870979 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 12, 2017 Nov 30, 2024 May 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004064.5:c.206C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004055.1:p.Pro69Leu missense NC_000012.12:g.12718045C>T NC_000012.11:g.12870979C>T NG_016341.1:g.5678C>T P46527:p.Pro69Leu - Protein change
- P69L
- Other names
- -
- Canonical SPDI
- NC_000012.12:12718044:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
- 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. |
|||
| CDKN1B | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
940 | 991 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
May 27, 2024 | RCV000162207.16 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 14, 2023 | RCV002415708.5 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001395064.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 4
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003823115.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002727686.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide … (more)
The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 206. The proline at codon 69 is replaced by leucine, an amino acid with similar properties. This variant has been reported in an individual with papillary thyroid carcinoma, nonfunctioning pituitary microadenoma, as well as other comorbidities; in vitro fuctional studies showed this variant resulted in consistently reduced expression and slightly faster degradation compared to wild type (Molatore S et al. Hum. Mutat., 2010 Nov;31:E1825-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(May 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 4
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV005045519.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Zygosity: Single Heterozygote
Age: 30-39 years
Sex: male
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 4
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005416189.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PP3_Strong+PS4_Supporting
|
|
|
Pathogenic
(Nov 01, 2010)
|
no assertion criteria provided
Method: literature only
|
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000212164.4
First in ClinVar: Mar 16, 2015 Last updated: Jan 26, 2024 |
Comment on evidence:
In a 79-year-old Caucasian woman with multiple endocrine neoplasia type IV (MEN4; 610755), Molatore et al. (2010) identified a heterozygous c.678C-T transition in the CDKN1B … (more)
In a 79-year-old Caucasian woman with multiple endocrine neoplasia type IV (MEN4; 610755), Molatore et al. (2010) identified a heterozygous c.678C-T transition in the CDKN1B gene, resulting in a pro69-to-leu (P69L) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP database or in 370 control individuals. In vitro cellular expression studies showed that the mutation caused reduced mutant protein levels due to more rapid degradation, as well as slightly higher cytoplasmic localization compared to wildtype. Molecular modeling indicated that the mutation affected a CDK2 (116953)-binding site, and immunoblot analysis confirmed that the mutant protein could not bind CDK2. The P69L mutant protein was less effective at suppressing growth of neuroendocrine tumor cells in vitro compared to wildtype. The patient had bronchial carcinoid, a nonfunctioning pituitary microadenoma, parathyroid adenoma, and papillary thyroid carcinoma. Both bronchial carcinoid and parathyroid adenoma tissue showed decreased or even absent p27 protein expression, but loss of heterozygosity for the wildtype CDKN1B allele was observed only in the carcinoid sample. (less)
|
Comment:
Comment:
The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 206. The proline at codon 69 is replaced by leucine, an amino acid with similar properties. This variant has been reported in an individual with papillary thyroid carcinoma, nonfunctioning pituitary microadenoma, as well as other comorbidities; in vitro fuctional studies showed this variant resulted in consistently reduced expression and slightly faster degradation compared to wild type (Molatore S et al. Hum. Mutat., 2010 Nov;31:E1825-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
PM2_Supporting+PP3_Strong+PS4_Supporting
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:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 206. The proline at codon 69 is replaced by leucine, an amino acid with similar properties. This variant has been reported in an individual with papillary thyroid carcinoma, nonfunctioning pituitary microadenoma, as well as other comorbidities; in vitro fuctional studies showed this variant resulted in consistently reduced expression and slightly faster degradation compared to wild type (Molatore S et al. Hum. Mutat., 2010 Nov;31:E1825-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
PM2_Supporting+PP3_Strong+PS4_Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multiple Endocrine Neoplasia Type 4: Novel CDNK1B variant and immune anomalies. | Chevalier B | Annales d'endocrinologie | 2020 | PMID: 32386678 |
| Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
| A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. | Molatore S | Human mutation | 2010 | PMID: 20824794 |
Text-mined citations for rs777354267 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Dec 07, 2024
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.