ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2T>A (p.Met1Lys)
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.
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(12); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.2T>A (p.Met1Lys)
Variation ID: 182809 Accession: VCV000182809.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6009018 (GRCh38) [ NCBI UCSC ] 7: 6048649 (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 Jun 3, 2016 May 1, 2024 Oct 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.2T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Met1Lys missense initiator codon variant NM_001322003.2:c.-399T>A 5 prime UTR NM_001322004.2:c.-264T>A 5 prime UTR NM_001322005.2:c.-594T>A 5 prime UTR NM_001322006.2:c.2T>A NP_001308935.1:p.Met1Lys missense initiator codon variant NM_001322007.2:c.-214T>A 5 prime UTR NM_001322008.2:c.-74T>A 5 prime UTR NM_001322009.2:c.-589T>A 5 prime UTR NM_001322010.2:c.-264T>A 5 prime UTR NM_001322011.2:c.-883T>A 5 prime UTR NM_001322012.2:c.-878T>A 5 prime UTR NM_001322013.2:c.-399T>A 5 prime UTR NM_001322014.2:c.2T>A NP_001308943.1:p.Met1Lys missense initiator codon variant NM_001322015.2:c.-478T>A 5 prime UTR NR_136154.1:n.89T>A non-coding transcript variant NC_000007.14:g.6009018A>T NC_000007.13:g.6048649A>T NG_008466.1:g.5089T>A NG_050738.1:g.4768A>T LRG_161:g.5089T>A LRG_161t1:c.2T>A - Protein change
- M1K
- Other names
- p.M1K:ATG>AAG
- Canonical SPDI
- NC_000007.14:6009017:A:T
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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
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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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 |
5177 | 5277 |
Conditions - Germline
Condition
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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
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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. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV000160895.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 6, 2023 | RCV000212834.12 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Apr 4, 2023 | RCV000500749.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2020 | RCV000781734.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763593.9 | |
PMS2-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2023 | RCV003407599.4 |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2019 | RCV004017444.1 |
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 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 4
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596477.2
First in ClinVar: Aug 28, 2017 Last updated: Sep 03, 2023 |
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Pathogenic
(Oct 27, 2017)
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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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Counsyl
Accession: SCV000785677.3
First in ClinVar: Aug 28, 2017 Last updated: Sep 03, 2023 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mismatch repair cancer syndrome 1
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894432.2
First in ClinVar: Mar 31, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Nov 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920019.3
First in ClinVar: Jun 02, 2019 Last updated: Sep 03, 2023 |
Comment:
Variant summary: PMS2 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: PMS2 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250260 control chromosomes (gnomAD). c.2T>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Chubb_2015, Susswein_2016). It has also been reported in compound heterozygous individuals affected with Constitutional Mismatch Repair-Deficiency syndrome with evidence of complete loss of PMS2 in both tumor and normal tissue following immunohistochemical staining (e.g. Adam_2016, Pavelka_2019). These data indicate that the variant is likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Other variants affecting the PMS2 initiation codon (e.g. c.1A>G, c.1A>T, c.2T>C) have been reported as disease-associated indicating the functional importance of this position. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000214325.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the PMS2 gene. This variant results from a T to … (more)
The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the PMS2 gene. This variant results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This alteration was previously identified in a patient with colon cancer and in a patient with CMMRD who had another PMS2 mutation in trans (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Adam R et al. Am. J. Hum. Genet. 2016 Aug;99(2):337-51). Other alterations impacting the PMS2 initiation codon have been reported in individuals with early-onset, Lynch syndrome-associated malignancies and tumors demonstrating isolated loss of PMS2 staining by immunohistochemistry (IHC) (Senter et al. Gastroenterology. 2008 Aug;135(2):419-28; Borràs E et al. J. Med. Genet. 2013 Aug; 50(8):552-63). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. (less)
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Uncertain significance
(May 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429095.2
First in ClinVar: Aug 16, 2020 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 2
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Likely pathogenic
(May 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579149.2
First in ClinVar: Oct 15, 2022 Last updated: Sep 03, 2023
Comment:
ACMG criteria applied: PVS1_MOD, PS4_MOD, PM3, PM2_SUP
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jun 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774370.2
First in ClinVar: Dec 31, 2022 Last updated: Sep 03, 2023 |
Comment:
This variant is located in the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The variant has … (more)
This variant is located in the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The variant has been reported in affected individuals with colorectal cancer in the published literature (PMIDs: 25559809 (2015) and 26681312 (2015)). This variant has also been reported in individuals with constitutional mismatch repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMIDs: 27476653 (2016) and 30764633 (2018)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211587.13
First in ClinVar: Feb 24, 2015 Last updated: Sep 03, 2023 |
Comment:
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Described as a pathogenic founder variant in the … (more)
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Described as a pathogenic founder variant in the Icelandic population (Haraldsdottir et al., 2017); Identified in the heterozygous state in an individual with a personal and family history of colorectal cancer (Chubb et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 27742654, 30787465, 31447099, 28466842, 25559809, 27476653, 29922827, 32719484, 33087929, 30764633) (less)
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Pathogenic
(Apr 04, 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: SCV004019807.2
First in ClinVar: Jul 29, 2023 Last updated: Sep 03, 2023 |
Comment:
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. … (more)
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30680046, 27476653, 18602922]. (less)
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Pathogenic
(Feb 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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PMS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108717.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PMS2 c.2T>A variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in the heterozygous state in patients … (more)
The PMS2 c.2T>A variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in the heterozygous state in patients with colorectal cancer (see for example Chubb et al. 2015. PubMed ID: 25559809; Susswein et al. 2016. PubMed ID: 26681312). This variant has also been reported in the compound heterozygous state in association with constitutional mismatch repair cancer syndrome (Adam et al. 2016. PubMed ID: 27476653). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6048649-A-T), and it is classified by the majority of submitters to ClinVar as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/182809/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818401.3
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000691064.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant results in the loss of the translation start codon of the PMS2 gene. Although functional studies have not been reported for this variant, … (more)
This variant results in the loss of the translation start codon of the PMS2 gene. Although functional studies have not been reported for this variant, it is expected to disrupt the expression of the full-length PMS2 protein. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 26681312) and in individuals affected with constitutional mismatch-repair deficiency who carried another pathogenic variant in PMS2 (PMID: 27476653, 30764633). This variant has been identified in 2/250260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions affecting the same start codon are considered to be disease-causing (ClinVar variation ID: 91323, 127788, 142777, 231873, 957082, 450786, 820477), suggesting that this start codon is critical for PMS2 translation. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Oct 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848312.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Met? (c.2T>A) variant in PMS2 has been previously reported in 1 individual with rectal cancer in the heterozygous state (Chubb 2015) and 1 individual … (more)
The p.Met? (c.2T>A) variant in PMS2 has been previously reported in 1 individual with rectal cancer in the heterozygous state (Chubb 2015) and 1 individual with constitutive mismatch repair deficiency in the compound heterozygous state (Adam 2016). It has been identified in 2/112800 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 182809), and classified as pathogenic by several clinical labs. This variant affects the translation initiation start codon (ATG) and is, therefore, predicted to disrupt translation. However, this exon is not present on all PMS2 transcripts. Therefore, the precise effect on the protein cannot be predicted, as this variant may lead to no protein synthesis or the activation of a downstream translation initiation codon, resulting in an alternative isoform. Other variants affecting this initiation codon have been reported in individuals with colorectal cancer and have been reported in ClinVar. In summary, the c.2T>A variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PS1, PM2, PM3. (less)
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Pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Lynch syndrome 4
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022255.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000535.7:c.2T>A (chr7:6009018) in PMS2 was detected in 51 heterozygotes out of 58K WGS Icelanders (MAF= 0,044%). Following imputation in a set of 166K … (more)
The variant NM_000535.7:c.2T>A (chr7:6009018) in PMS2 was detected in 51 heterozygotes out of 58K WGS Icelanders (MAF= 0,044%). Following imputation in a set of 166K Icelanders (144 imputed heterozygotes) we observed an association with colorectal cancer using 4991 cases and 314812 controls (OR= 2.25, P= 4.86e-02). This variant has been reported in ClinVar previously as pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PVS1, PS4) this variant classifies as pathogenic. (less)
Number of individuals with the variant: 144
Ethnicity/Population group: Icelandic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
Effective Immunotherapy of Glioblastoma in an Adolescent with Constitutional Mismatch Repair-Deficiency Syndrome. | Pavelka Z | Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti | 2019 | PMID: 30764633 |
Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes. | Henn J | Hereditary cancer in clinical practice | 2019 | PMID: 30680046 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. | Haraldsdottir S | Nature communications | 2017 | PMID: 28466842 |
Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. | Adam R | American journal of human genetics | 2016 | PMID: 27476653 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. | Chubb D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25559809 |
Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. | Borràs E | Journal of medical genetics | 2013 | PMID: 23709753 |
The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. | Senter L | Gastroenterology | 2008 | PMID: 18602922 |
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Text-mined citations for rs587780059 ...
HelpRecord last updated Jun 30, 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.