ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1906G>C (p.Ala636Pro)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.1906G>C (p.Ala636Pro)
Variation ID: 1764 Accession: VCV000001764.46
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p21 2: 47475171 (GRCh38) [ NCBI UCSC ] 2: 47702310 (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 Apr 4, 2013 Aug 25, 2024 Sep 5, 2013 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000251.3:c.1906G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ala636Pro missense NM_001258281.1:c.1708G>C NP_001245210.1:p.Ala570Pro missense NC_000002.12:g.47475171G>C NC_000002.11:g.47702310G>C NG_007110.2:g.77048G>C LRG_218:g.77048G>C LRG_218t1:c.1906G>C LRG_218p1:p.Ala636Pro P43246:p.Ala636Pro - Protein change
- A636P, A570P
- Other names
- p.A636P:GCA>CCA
- Canonical SPDI
- NC_000002.12:47475170:G:C
-
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.
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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. |
|||
MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7401 | 7563 |
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 (4) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000030245.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2023 | RCV000130428.15 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 30, 2022 | RCV000202220.23 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2023 | RCV000376757.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 30, 2023 | RCV000524366.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763493.2 | |
Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353396.2 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Sep 05, 2013)
|
reviewed by expert panel
Method: research
|
Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107338.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comment:
Abrogated function & CMMRD, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Muir-Torré syndrome Mismatch repair cancer syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894279.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
|
Hereditary non-polyposis colon cancer
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052912.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 5
Observation 2:
Number of individuals with the variant: 2
Observation 3:
Number of individuals with the variant: 16
Observation 4:
Tissue: Blood
Observation 5:
Tissue: Blood
|
|
Pathogenic
(Nov 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677734.2
First in ClinVar: Jan 06, 2018 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211191.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: reduced DNA repair efficiency and partial loss of function suggesting impact on MSH2 protein folding (Foulkes et al., … (more)
Published functional studies demonstrate a damaging effect: reduced DNA repair efficiency and partial loss of function suggesting impact on MSH2 protein folding (Foulkes et al., 2002; Ollila et al., 2006; Drost et al., 2012; Houlleberghs et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22102614, 26951660, 25307252, 18674656, 28790115, 15845562, 16199548, 19267393, 18566915, 23990280, 25117503, 24362816, 22949387, 22949379, 21120944, 18951462, 17594722, 10528862, 17101317, 15516845, 26440929, 26544533, 27013479, 27601186, 27720647, 22045683, 22516243, 14668545, 28422960, 28526081, 28514183, 28510494, 12454801, 26681312, 28135145, 15872200, 20388775, 19101824, 18822302, 30572730, 29961768, 30152102, 29506128, 30702970, 30998989, 31857677, 31730237, 31491536, 31447099, 31615790, 32489267, 31948886, 30787465, 26556299, 33357406, 27535533, 25025451) (less)
|
|
Pathogenic
(Aug 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257157.3
First in ClinVar: Nov 20, 2015 Last updated: Jun 03, 2023 |
Comment:
PP1, PP5, PM3, PS3, PS4_moderate
|
|
Pathogenic
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018425.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10528862, 12454801].
|
|
Pathogenic
(Mar 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601446.4
First in ClinVar: Mar 08, 2017 Last updated: Jan 06, 2024 |
Comment:
The variant has been reported in symptomatic individuals with colorectal, prostate, or endometrial cancer and in individuals affected with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome … (more)
The variant has been reported in symptomatic individuals with colorectal, prostate, or endometrial cancer and in individuals affected with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (PMIDs: 12454801 (2002), 19101824 (2009), 21419771 (2011), 23990280 (2014), and 25117503 (2014)). In addition, functional studies have shown that this variant has a deleterious effect on MSH2 mismatch repair activity (PMIDs: 17101317 (2006), 18951462 (2008), 22102614 (2012), and 26951660 (2016)). This variant is a founder mutation in the Ashkenazi Jewish population (PMIDs: 12454801 (2002), 16199548 (2005), 21419771 (2011), and 22949379 (2013)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Jan 03, 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: SCV000684993.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with proline at codon 636 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces alanine with proline at codon 636 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant abolishes MMR activity in vitro (PMID: 17101317, 22102614), impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406), and causes deficient DNA binding (PMID: 18951462). This variant is known to be a founder mutation in Ashkenazi Jewish population and has been reported in up to 30% of families affected with Lynch syndrome (PMID: 12454801, 21419771, 23990280). This variant has also been observed in the homozygous state in individuals showing symptoms consistent with constitutional mismatch repair deficiency (PMID: 19101824, 23990280). This variant has been identified in 5/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185292.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.A636P pathogenic mutation (also known as c.1906G>C), located in coding exon 12 of the MSH2 gene, results from a G to C substitution at … (more)
The p.A636P pathogenic mutation (also known as c.1906G>C), located in coding exon 12 of the MSH2 gene, results from a G to C substitution at nucleotide position 1906. The alanine at codon 636 is replaced by proline, an amino acid with highly similar properties. This alteration represents an Ashkenazi Jewish founder mutation identified in numerous families meeting criteria for Lynch syndrome with supporting MSI/IHC tumor data (Yuan ZQ et al. J. Med. Genet. 1999 Oct;36:790-3; Foulkes WD et al. Am. J. Hum. Genet. 2002 Dec;71:1395-412; Sun S et al. J. Med. Genet. 2005 Oct;42:766-8; Goldberg Y et al. Fam. Cancer. 2014 Mar;13:65-73; Ambry Internal Data). It has also been identified in an individual with constitutional mismatch repair-deficiency (CMMR-D) syndrome who was homozygous for this alteration (Toledano H et al. Fam. Cancer. 2009;8:187-94). Functional assays and structural modeling indicate this alteration would have a deleterious impact on mismatch repair (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation. (less)
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199180.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
Pathogenic
(Jan 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331841.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
Pathogenic
(Oct 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary non-polyposis colorectal cancer, type 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434866.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.1906G>C (p.Ala636Pro) variant in the MSH2 gene has been reported in multiple Ashkenazi Jewish families affected with Lynch Syndrome (PMID 10528862, 12454801, 17101317,21419771) and … (more)
The c.1906G>C (p.Ala636Pro) variant in the MSH2 gene has been reported in multiple Ashkenazi Jewish families affected with Lynch Syndrome (PMID 10528862, 12454801, 17101317,21419771) and segregates with disease in multiple families (PMID 10528862, 12454801). The overall hazardous ratio of developing colorectal cancer is 31.8 for men and 41.8 for women. The overall hazardous ratio of developing endometrial cancer is 66.7 (PMID 21419771) . Tumors from multiple index patients showed microsatellite instability with loss of MSH2 expression (PMID 12454801, 17101317). Functional studies suggest that this variant leads to DNA binding deficiency (PMID 18951462). Therefore, this c.1906G>C (p.Ala636Pro) variant in the MSH2 gene is classified as pathogenic. (less)
|
|
Pathogenic
(Nov 25, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534424.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.1906G>C (p.A636P) is a well-known pathogenic variant associated with Lynch syndrome in the Ashkenazi Jewish population that has been reported in heterozygosity in … (more)
The MSH2 c.1906G>C (p.A636P) is a well-known pathogenic variant associated with Lynch syndrome in the Ashkenazi Jewish population that has been reported in heterozygosity in at least 27 individuals with Colorectal Cancer (PMID: 16199548, 15872200, 15845562, 12454801, 10528862, 17414604). This variant was also reported homozygous in 3 individuals with constitutional mismatch repair deficiency (PMID: 19101824, 23990280). Functional studies have shown that this variant is deficient in MMR repair (PMID: 15872200). This variant was observed in 3/10370 chromosomes in the Ashkenazi Jewish population, with 0 homozygotes, according to the Genome Aggregation Database (PMID: 27535533). This variant has been classified as pathogenic by a ClinGen-approved expert panel. Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Dec 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166268.14
First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 636 of the MSH2 protein (p.Ala636Pro). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 636 of the MSH2 protein (p.Ala636Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with symptoms consistent with constitutional mismatch repair deficiency (PMID: 12454801, 19101824, 21419771, 23990280). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 12454801, 21419771, 23990280). ClinVar contains an entry for this variant (Variation ID: 1764). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462, 22102614). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004829840.1
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)
|
Comment:
The c.1906G>C (p.Ala636Pro) variant in the MSH2 gene has been reported in multiple individuals affected with Lynch Syndrome, colorectal cancer, prostate cancer, endometrial cancer, and … (more)
The c.1906G>C (p.Ala636Pro) variant in the MSH2 gene has been reported in multiple individuals affected with Lynch Syndrome, colorectal cancer, prostate cancer, endometrial cancer, and Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (PMID 10528862, 12454801, 17101317, 19101824, 21419771, 23990280, 25117503). This variant segregates with disease in multiple families (PMID 10528862, 12454801). This variant is known to be a founder variant in the Ashkenazi Jewish population (PMID: 12454801, 16199548, 21419771, 22949379, 23990280). This variant has also been reported in homozygous state in individuals with CMMRD (PMID: 19101824, 23990280). Tumors from multiple individuals showed microsatellite instability with loss of MSH2 expression (PMID 12454801, 17101317). Functional studies suggest that this variant leads to DNA binding deficiency and affects MSH2 mismatch repair activity (PMID: 15872200, 17101317, 18951462, 20850175, 22102614, 26951660). This variant has been identified in 5/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Therefore, this c.1906G>C (p.Ala636Pro) variant in the MSH2 gene is classified as pathogenic. (less)
Number of individuals with the variant: 5
|
|
Pathogenic
(Oct 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847553.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ala636Pro variant in MSH2 is a well-known founder variant, having been reported in many Ashkenazi Jewish individuals with Lynch syndrome and having been shown … (more)
The p.Ala636Pro variant in MSH2 is a well-known founder variant, having been reported in many Ashkenazi Jewish individuals with Lynch syndrome and having been shown to segregate with disease in multiple families (Foulkes 2002 PMID: 12454801, Mukherjee 2011 PMID: 21419771, Dominguez-Valentin 2016 PMID: 27013479). Tumors from multiple index patients showed microsatellite instability with loss of MSH2 expression (Foulkes 2002 PMID 12454801, Ollila 2006 PMID:17101317). This variant has also been identified in 0.03% (3/10370) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Multiple in vitro functional studies provide some evidence that this variant impacts protein function (Yuan 1999 PMID:10528862, Ollila 2006 PMID: 17101317, Houlleberghs 2016 PMID: 26951660). Additionally, this variant has also been observed in the homozygous state in individuals with symptoms consistent with constitutional mismatch repair deficiency (CMMRD). Moreover, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID: 1764). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Strong, PP1_Strong, PS3_Moderate, PM2_Supporting. (less)
|
|
Pathogenic
(Nov 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004193909.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592524.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Ala636Pro variant was identified in 19 of 3058 proband chromosomes (frequency: 0.006) from individuals or families with colorectal, ovarian and endometrial cancers in … (more)
The MSH2 p.Ala636Pro variant was identified in 19 of 3058 proband chromosomes (frequency: 0.006) from individuals or families with colorectal, ovarian and endometrial cancers in Ashkenazi Jewish individuals, and was not identified in 3176 control chromosomes from healthy individuals. Functional studies showed that the addition of a single human chromosome containing the variant did not correct mismatch repair deficiency in MSH2 mouse cells confirming that this variant is a bona fide disease causing mutation. In addition, immunohistochemical data show that the protein is unstable (Foulkes 2002, Barak 2010, Durno 2005, Fidder 2005). The variant was also identified by our laboratory in 1 individual with ovarian cancer. The variant was further identified in dbSNP (ID: rs63750875) “With Pathogenic Allele”, in Exome Aggregation Consortium database (August 8, 2016) in 1 of 121410 chromosomes (freq. 000008) in the following population: 1 of 66740 chromosomes European (Non-Finnish) (freq. 0.00002); it was not seen in African, East Asian, European (Finnish), Latino populations and South Asian Populations. The variant was also identified in ClinVar and ClinVitae as pathogenic by Insight, Invitae, Ambry Genetics, GeneDx, LabCorp, OMIM and the Mayo Clinic Genetic Testing Laboratories; UMD 14X as Casual; InSiGHT Colon Cancer Gene Variant Database (LOVD), 52X as Class 5, and in MMR Gene Unclassified Variants Databases. The variant was not identified in the COGR, COSMIC, MutDB, Zhejiang Colon Cancer d(LOVD) databases or in the 1000 Genomes and NHLBI GO Exome Sequencing Projects. The p.Ala636 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
Pathogenic
(Oct 01, 2005)
|
no assertion criteria provided
Method: literature only
|
LYNCH SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021990.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In an Ashkenazi kindred with hereditary nonpolyposis colorectal cancer type 1 (LYNCH1; 120435), Yuan et al. (1999) found a G-to-C transversion in the MSH2 gene, … (more)
In an Ashkenazi kindred with hereditary nonpolyposis colorectal cancer type 1 (LYNCH1; 120435), Yuan et al. (1999) found a G-to-C transversion in the MSH2 gene, resulting in an ala636-to-pro (A636P) substitution segregating with the disease. In addition, they found a missense mutation in the APC gene (I1307K; 175100.0029) in 2 unaffected members of the kindred. Yuan et al. (1999) concluded that clinical surveillance for CRC should not be discontinued in Ashkenazi families with HNPCC where an MSH2 mutation had been found until the APC gene had also been analyzed, and that the APC I1307K mutation should be sought in Ashkenazi families with multiple cases of CRC. Yuan et al. (1999) also recognized that the relationship between the presence of that mutation and CRC was not fully resolved. Foulkes et al. (2002) stated that the 1906G-C mutation had been found in 25 apparently unrelated Ashkenazi Jewish families. It was estimated to account for 2 to 3% of colorectal cancer in those whose age at diagnosis was less than 60 years. The mutation was highly penetrant and accounted for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfilled the Amsterdam criteria. Using an intraallelic coalescent model of multipoint linkage disequilibrium mapping, Sun et al. (2005) determined that the 1906G-C founder mutation probably originated between 1440 and 1715 in the Ashkenazi Jewish population, at a time when the Ashkenazim were living in eastern Europe in partially closed communities. (less)
|
|
Pathogenic
(Sep 16, 2018)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809450.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV002054074.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer. | Aronson M | Current oncology (Toronto, Ont.) | 2020 | PMID: 32489267 |
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. | Hechtman JF | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 31857677 |
Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. | Wischhusen JW | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 31615790 |
The spectrum of Lynch syndrome-associated germ-line mutations in Russia. | Yanus GA | European journal of medical genetics | 2020 | PMID: 31491536 |
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 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. | Yurgelun MB | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29961768 |
Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations. | Cox DM | Molecular genetics & genomic medicine | 2018 | PMID: 30152102 |
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. | Lowery MA | Journal of the National Cancer Institute | 2018 | PMID: 29506128 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. | Dominguez-Valentin M | BMC urology | 2016 | PMID: 27013479 |
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants. | Houlleberghs H | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 26951660 |
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 |
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
Identification of germline genetic mutations in patients with pancreatic cancer. | Salo-Mullen EE | Cancer | 2015 | PMID: 26440929 |
The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer. | Levi Z | Clinical genetics | 2015 | PMID: 25307252 |
High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. | Rosty C | Familial cancer | 2014 | PMID: 25117503 |
The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy. | Chui MH | The American journal of surgical pathology | 2014 | PMID: 25025451 |
Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). | Wimmer K | Journal of medical genetics | 2014 | PMID: 24737826 |
Lynch Syndrome in high risk Ashkenazi Jews in Israel. | Goldberg Y | Familial cancer | 2014 | PMID: 23990280 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. | Karamurzin Y | Human pathology | 2012 | PMID: 22516243 |
A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation. | Mukherjee B | Gastroenterology | 2011 | PMID: 21419771 |
The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients. | Barak F | Gynecologic oncology | 2010 | PMID: 20850175 |
Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. | Shah SN | Cancer research | 2010 | PMID: 20068152 |
Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. | Arnold S | Human mutation | 2009 | PMID: 19267393 |
Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. | Toledano H | Familial cancer | 2009 | PMID: 19101824 |
Mechanisms of pathogenicity in human MSH2 missense mutants. | Ollila S | Human mutation | 2008 | PMID: 18951462 |
Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation. | Lavie O | American journal of obstetrics and gynecology | 2008 | PMID: 18674656 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: role in presurgical management. | Guillem JG | Annals of surgery | 2007 | PMID: 17414604 |
Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. | Ollila S | Gastroenterology | 2006 | PMID: 17101317 |
The HNPCC associated MSH2*1906G-->C founder mutation probably originated between 1440 CE and 1715 CE in the Ashkenazi Jewish population. | Sun S | Journal of medical genetics | 2005 | PMID: 16199548 |
Clinical and genetic findings in an Ashkenazi Jewish population with colorectal neoplasms. | Zauber NP | Cancer | 2005 | PMID: 15959913 |
Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). | Hampel H | The New England journal of medicine | 2005 | PMID: 15872200 |
Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma. | Durno C | Gut | 2005 | PMID: 15845562 |
Localization of cancer susceptibility genes by genome-wide single-nucleotide polymorphism linkage-disequilibrium mapping. | Mitra N | Cancer research | 2004 | PMID: 15520224 |
A636P testing in Ashkenazi Jews. | Guillem JG | Familial cancer | 2004 | PMID: 15516845 |
The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. | Foulkes WD | American journal of human genetics | 2002 | PMID: 12454801 |
Phenotypic analysis of hMSH2 mutations in mouse cells carrying human chromosomes. | Marra G | Cancer research | 2001 | PMID: 11691782 |
A missense mutation in both hMSH2 and APC in an Ashkenazi Jewish HNPCC kindred: implications for clinical screening. | Yuan ZQ | Journal of medical genetics | 1999 | PMID: 10528862 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH2 | - | - | - | - |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.1906G%3EC | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs63750875 ...
HelpRecord 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.