Variant summary: The PMS2 c.1164delT (p.His388Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate C-terminal MutL dimerisation domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1831dupA/p.Ile611fs). This variant has been reported in two siblings with constitutive mismatch repair deficiency in homozygous state, their parents being heterozygous carriers for the variant. The variant is absent in 115240 control chromosomes from ExAC. Taken together, this variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1164del (p.His388fs)
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.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.1164del (p.His388fs)
Variation ID: 480324 Accession: VCV000480324.13
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5987601 (GRCh38) [ NCBI UCSC ] 7: 6027232 (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 Feb 19, 2018 May 1, 2024 Sep 20, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.1164del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.His388fs frameshift NM_000535.6:c.1164del NM_001322003.2:c.759del NP_001308932.1:p.His253fs frameshift NM_001322004.2:c.759del NP_001308933.1:p.His253fs frameshift NM_001322005.2:c.759del NP_001308934.1:p.His253fs frameshift NM_001322006.2:c.1008del NP_001308935.1:p.His336fs frameshift NM_001322007.2:c.846del NP_001308936.1:p.His282fs frameshift NM_001322008.2:c.846del NP_001308937.1:p.His282fs frameshift NM_001322009.2:c.759del NP_001308938.1:p.His253fs frameshift NM_001322010.2:c.603del NP_001308939.1:p.His201fs frameshift NM_001322011.2:c.231del NP_001308940.1:p.His77fs frameshift NM_001322012.2:c.231del NP_001308941.1:p.His77fs frameshift NM_001322013.2:c.591del NP_001308942.1:p.His197fs frameshift NM_001322014.2:c.1164del NP_001308943.1:p.His388fs frameshift NM_001322015.2:c.855del NP_001308944.1:p.His285fs frameshift NR_136154.1:n.1251del non-coding transcript variant NC_000007.14:g.5987601del NC_000007.13:g.6027232del NG_008466.1:g.26506del LRG_161:g.26506del LRG_161t1:c.1164del - Protein change
- H201fs, H282fs, H285fs, H336fs, H388fs, H197fs, H77fs, H253fs
- Other names
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- Canonical SPDI
- NC_000007.14:5987600: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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- 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. |
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| PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5326 | 5429 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Mar 2, 2022 | RCV000570757.9 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2022 | RCV002526794.3 | |
| Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2016 | RCV000587567.1 | |
| Pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2023 | RCV003451228.1 |
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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Pathogenic
(Aug 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Turcot syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697281.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PMS2 c.1164delT (p.His388Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense … (more)
Variant summary: The PMS2 c.1164delT (p.His388Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate C-terminal MutL dimerisation domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1831dupA/p.Ile611fs). This variant has been reported in two siblings with constitutive mismatch repair deficiency in homozygous state, their parents being heterozygous carriers for the variant. The variant is absent in 115240 control chromosomes from ExAC. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000691001.3
First in ClinVar: Feb 19, 2018 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 02, 2021)
|
criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529761.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.1164delT (p.H388QfsX10) variant has been reported as homozygous in at least two families with constitutional mismatch repair deficiency syndrome (PMID: 23629955, 31599855). Tumors … (more)
The PMS2 c.1164delT (p.H388QfsX10) variant has been reported as homozygous in at least two families with constitutional mismatch repair deficiency syndrome (PMID: 23629955, 31599855). Tumors found in these patients exhibit loss of PMS2 protein expression (PMID: 23629955).This variant causes a frameshift at amino acid 388 that results in premature termination 10 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004188573.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Nov 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003440125.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480324). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480324). This premature translational stop signal has been observed in individual(s) with autosomal recessive PMS2-related conditions (PMID: 23629955). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His388Glnfs*10) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). (less)
|
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Pathogenic
(Mar 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000663496.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.1164delT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1164, causing … (more)
The c.1164delT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1164, causing a translational frameshift with a predicted alternate stop codon (p.H388Qfs*10). This pathogenic mutation has been reported in a homozygous state in two siblings with constitutive mismatch repair deficiency (CMMR-D) syndrome; both parents were heterozygous for this mutation however their clinical histories were not provided (Chmara M et al. Genes Chromosomes Cancer 2013 Jul; 52(7):656-64). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480324). This premature translational stop signal has been observed in individual(s) with autosomal recessive PMS2-related conditions (PMID: 23629955). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His388Glnfs*10) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
Comment:
The c.1164delT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1164, causing a translational frameshift with a predicted alternate stop codon (p.H388Qfs*10). This pathogenic mutation has been reported in a homozygous state in two siblings with constitutive mismatch repair deficiency (CMMR-D) syndrome; both parents were heterozygous for this mutation however their clinical histories were not provided (Chmara M et al. Genes Chromosomes Cancer 2013 Jul; 52(7):656-64). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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:
Variant summary: The PMS2 c.1164delT (p.His388Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate C-terminal MutL dimerisation domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1831dupA/p.Ile611fs). This variant has been reported in two siblings with constitutive mismatch repair deficiency in homozygous state, their parents being heterozygous carriers for the variant. The variant is absent in 115240 control chromosomes from ExAC. Taken together, this variant is classified as Pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480324). This premature translational stop signal has been observed in individual(s) with autosomal recessive PMS2-related conditions (PMID: 23629955). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His388Glnfs*10) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
Comment:
The c.1164delT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1164, causing a translational frameshift with a predicted alternate stop codon (p.H388Qfs*10). This pathogenic mutation has been reported in a homozygous state in two siblings with constitutive mismatch repair deficiency (CMMR-D) syndrome; both parents were heterozygous for this mutation however their clinical histories were not provided (Chmara M et al. Genes Chromosomes Cancer 2013 Jul; 52(7):656-64). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report. | Sağ E | Journal of pediatric hematology/oncology | 2020 | PMID: 31599855 |
| Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
| Multiple pilomatricomas with somatic CTNNB1 mutations in children with constitutive mismatch repair deficiency. | Chmara M | Genes, chromosomes & cancer | 2013 | PMID: 23629955 |
| Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines. | Herkert JC | European journal of cancer (Oxford, England : 1990) | 2011 | PMID: 21376568 |
Text-mined citations for rs1554298082 ...
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 Sep 29, 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.