ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2437A>G (p.Met813Val) (rs63749841)

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Total submissions: 9
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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 I 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 I 2015-12-12 criteria provided, single submitter clinical testing
Invitae RCV000524387 SCV000548286 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 813 of the MSH2 protein (p.Met813Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs63749841, ExAC 0.003%). This variant has been reported one family with suspected Lynch syndrome; however, the variant did not segregate with disease in this family (PMID: 12373605, 24501230). ClinVar contains an entry for this variant (Variation ID: 90972). Experimental studies have shown that this variant does not adversely affect the mismatch repair activity of the MSH2 protein (PMID: 24501230). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000570186 SCV000673874 likely benign Hereditary cancer-predisposing syndrome 2017-01-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
Color RCV000570186 SCV000685043 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000790629 SCV000696250 uncertain significance not specified 2019-04-30 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 (gnomAD). 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 (Wielders_2014, Gille_2002). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.1961delA, p.Lys654fsX47, internal testing), 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 (Wielders_2014, Gille_2002). These data provide further supporting evidence for a benign role of the variant. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (2x) while an expert panel (InSiGHT), following a recent reclassification, cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000411724 SCV001135759 benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148639 SCV000190354 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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