Submissions for variant NM_000251.3(MSH2):c.2437A>G (p.Met813Val)

gnomAD frequency: 0.00001  dbSNP: rs63749841

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000411724	SCV000107504	uncertain significance	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3.
GeneDx	RCV000586466	SCV000149427	uncertain significance	not provided	2018-06-19	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2437A>G at the cDNA level, p.Met813Val (M813V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been identified in at least one individual with colon cancer whose tumor was shown to be microsatellite stable and exhibit expression of all four mismatch repair proteins on immunohistochemistry (Gille 2002, Wielders 2014). Functional assays conducted in mouse embryonic stem cells demonstrated that this variant displayed protein expression and mismatch repair activity comparable to wild type (Wielders 2014). MSH2 Met813Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Met813Val is located in the ATPase domain (Lutzen 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MSH2 Met813Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000411724	SCV000488011	likely benign	Lynch syndrome 1	2015-12-12	criteria provided, single submitter	clinical testing
Invitae	RCV000524387	SCV000548286	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570186	SCV000673874	likely benign	Hereditary cancer-predisposing syndrome	2018-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000570186	SCV000685043	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 813 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). In another functional study, this variant caused no significant difference in microsatellite levels or DNA damage response compared to wild type (PMID: 24501230). This variant has been reported in individuals affected by colorectal cancer but with clinical features not indicative of Lynch syndrome (the tumors exhibited microsatellite stability and the presence of MSH2 protein (PMID: 12373605, 24501230)) and in individuals affected with cancer who did not meet Bethesda Lynch syndrome criteria (PMID: 31386297). This variant has been identified in 3/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000790629	SCV000696250	uncertain significance	not specified	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2437A>G (p.Met813Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2437A>G has been reported in the literature in suspected or affected Lynch Syndrome individuals/families (example: Gille_2002, Wielders_2014, Kiyozumi_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.1961delA, p.Lys654fsX47; ATM c.2921+1G>T), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated no reduction in protein level and no functional MMR defects for p.M813V and determined it to have similar function to the wild type. Furthermore, tumor analysis showed microsatellite stability and the presence of all four MMR proteins (Gille_2002, Wielders_2014). An additional study shows a neutral effect of the protein (Jia_2021). These data provide further supporting evidence for a benign role of the variant. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 18383312, 12373605, 33357406, 31386297, 24501230). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; seven submitters classified it as a variant of uncertain significance, two classified it as liekly benign, and one classified it as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000411724	SCV001135759	uncertain significance	Lynch syndrome 1	2023-06-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586466	SCV002046198	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with Lynch syndrome (PMIDs: 31386297 (2019), 24501230 (2014), 12373605 (2002)) and healthy, unaffected individuals (PMID: 25637381 (2018)). Experimental studies report the variant does not impact MSH2 function (PMIDs: 33357406 (2021), 24501230 (2014)). The frequency of this variant in the general population, 0.000026 (3/113690 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000411724	SCV004018395	uncertain significance	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000411724	SCV004196897	uncertain significance	Lynch syndrome 1	2022-09-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017386	SCV004848542	uncertain significance	Lynch syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The c.2437A>G (p.Met813Val) variant in MSH2 has been reported in 2 individuals with clinical features of Lynch syndrome (Gille 2002 PMID: 12373605, Wielders 2014 PMID: 24501230). It has also been identified in 0.003% (3/113690) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 90972). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro and in vivo functional studies provide some evidence that this variant does not impact protein function (Wielders 2014 PMID: 24501230), and a tumor derived from a patient with this variant was shown to be microsatellite stable (Gille 2002 PMID: 12373605). In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS3, BS1_Supporting.
CSER _CC_NCGL, University of Washington	RCV000148639	SCV000190354	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research