Submissions for variant NM_000251.3(MSH2):c.1906G>C (p.Ala636Pro)

gnomAD frequency: 0.00003  dbSNP: rs63750875

Total submissions: 21

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2023-12-30	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000130428	SCV000185292	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-11	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; 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.
GeneDx	RCV000202220	SCV000211191	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	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)
Mayo Clinic Laboratories, Mayo Clinic	RCV000202220	SCV000257157	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing	PP1, PP5, PM3, PS3, PS4_moderate
Eurofins Ntd Llc (ga)	RCV000202220	SCV000331841	pathogenic	not provided	2016-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202220	SCV000601446	pathogenic	not provided	2021-03-02	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000376757	SCV000677734	pathogenic	Lynch syndrome 1	2015-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130428	SCV000684993	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000763493	SCV000894279	pathogenic	Lynch syndrome 1; Mismatch repair cancer syndrome 1; 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 1	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.
Sema4, Sema4	RCV000130428	SCV002534424	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000376757	SCV004018425	pathogenic	Lynch syndrome 1	2023-03-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10528862, 12454801].
Baylor Genetics	RCV000376757	SCV004193909	pathogenic	Lynch syndrome 1	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030245	SCV004829840	pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030245	SCV004847553	pathogenic	Lynch syndrome	2021-10-27	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000376757	SCV000021990	pathogenic	Lynch syndrome 1	2005-10-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353396	SCV000592524	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	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.
Gharavi Laboratory, Columbia University	RCV000202220	SCV000809450	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
GeneReviews	RCV000376757	SCV002054074	not provided	Lynch syndrome 1		no assertion provided	literature only