ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1906G>C (p.Ala636Pro) (rs63750875)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030245 SCV000107338 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function & CMMRD, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Integrated Genetics/Laboratory Corporation of America RCV000030245 SCV000052912 pathogenic Lynch syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000524366 SCV000166268 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 636 of the MSH2 protein (p.Ala636Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs63750875, ExAC 0.001%). This variant is a known cause of hereditary nonpolyposis colorectal cancer (HNPCC) in the Ashkenazi Jewish population, accounting for 20-30% of HNPCC in families that fulfill the Amsterdam criteria (PMID: 12454801, 21419771, 23990280). This variant has also been observed in the homozygous state in individuals with symptoms consistent with constitutional mismatch repair deficiency (PMID: 19101824, 23990280). ClinVar contains an entry for this variant (Variation ID: 1764) Experimental studies have shown that this missense change disrupts the function of the MSH2 protein, rendering it defective in mismatch repair activity (PMID: 18951462, 17101317, 22102614). In addition, in silico computational models predict that this variant is pathogenic (PMID: 22949379, 22949387, 18383312). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000130428 SCV000185292 pathogenic Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing 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). 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 []). Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000202220 SCV000211191 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1906G>C at the cDNA level, p.Ala636Pro (A636P) at the protein level, and results in the change of an Alanine to a Proline (GCA>CCA). MSH2 Ala636Pro, a founder pathogenic variant in the Ashkenazi Jewish population, has been identified in many individuals with Lynch syndrome or a family history of Lynch-syndrome related tumors, as well as in the homozygous state in individuals with constitutional mismatch repair deficiency syndrome (Yuan 1999, Foulkes 2002, Guillem 2004, Lavie 2008, Toledano 2009). Tumor studies in multiple individuals with MSH2 Ala636Pro showed microsatellite instability (MSI-H) and absence of MSH2 protein expression (Ollila 2006, Toledano 2009, Kansikas 2011). MSH2 Ala636Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain and the region of interaction with EXO1 (Lutzen 2008, Kansikas 2011). Although in silico analysis predicts that this variant does not alter protein structure/function, multiple functional assays demonstrated reduced DNA repair efficiency and partial loss of function suggesting impact on MSH2 protein folding (Yuan 1999, Foulkes 2002, Ollila 2006, Houlleberghs 2016). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on multifactorial likelihood analysis (Thompson 2014). Based on currently available evidence, we consider this variant to be pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000202220 SCV000331841 pathogenic not provided 2016-01-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000030245 SCV000592524 pathogenic Lynch syndrome 2012-11-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202220 SCV000601446 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing
Counsyl RCV000376757 SCV000677734 pathogenic Lynch syndrome I 2015-11-10 criteria provided, single submitter clinical testing
Color RCV000130428 SCV000684993 pathogenic Hereditary cancer-predisposing syndrome 2020-02-07 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000202220 SCV000809450 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000763493 SCV000894279 pathogenic Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000376757 SCV001434866 pathogenic Lynch syndrome I 2018-10-15 criteria provided, single submitter clinical testing 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.
OMIM RCV000376757 SCV000021990 pathogenic Lynch syndrome I 2005-10-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202220 SCV000257157 pathogenic not provided no assertion criteria provided clinical testing

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