ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1774A>G (p.Met592Val) (rs371614039)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656879 SCV000211190 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1774A>G at the cDNA level, p.Met592Val (M592V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in an individual with a personal and/or family history suggestive of Lynch syndrome as well as two individuals with a personal and family history of colon cancer diagnosed after the age of 50 (Nilbert 2009, Chubb 2015). MSH2 Met592Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Met592Val is located in the lever domain and the region of interaction with MSH3 and MSH6 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Met592Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160595 SCV000212842 likely benign Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Structural Evidence
Invitae RCV000524360 SCV000261045 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 592 of the MSH2 protein (p.Met592Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs371614039, ExAC 0.002%). This variant has been reported in an individual with a personal and/or family history suggestive of Lynch syndrome (PMID: 18566915). It was also observed in two individuals with colon cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 90782). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. However, algorithms developed specifically for the MSH2 gene output conflicting predictions for the effect of this missense change (PMID: 18383312, 22290698). These predictions have not been confirmed by published functional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212609 SCV000539690 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3VUS (including expert panel), no new evidence since expert classification
Color Health, Inc RCV000160595 SCV000684975 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Counsyl RCV000662460 SCV000784941 uncertain significance Lynch syndrome I 2017-02-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212609 SCV001623207 uncertain significance not specified 2021-04-28 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1774A>G (p.Met592Val) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1774A>G has been reported in the literature in individuals affected with suspected Lynch Syndrome, colorectal cancer, and breast cancer (e.g. Nilbert_2009, Chubb_2015, Wu_2019, Ackay_2021, Banderia_2021). These reports, however, do not provide strong evidence for causality or unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories cited the variant as likely benign (n=1) and uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357833 SCV001553420 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Met592Val variant was identified in 3 of 3368 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome or colorectal cancer (Chubb 2015, Nilbert 2009). The variant was also identified in dbSNP (ID: rs371614039) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx and four other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 277192 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 126706 chromosomes (freq: 0.00006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met592 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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