ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1474A>G (p.Met492Val) (rs61754783)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587662 SCV000149283 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1474A>G at the cDNA level, p.Met492Val (M492V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). Although this variant was observed in three individuals with colorectal cancer from families suspicious for Lynch syndrome, as well as at least one individual with ovarian cancer (Wagner 2003, Nilbert 2009, Okkels 2012, Pal 2012), in vitro analysis demonstrated mismatch repair activity comparable to wild-type (Drost 2012). This variant has also been reported in individuals with pancreatic neuroendocrine tumor, breast cancer, or thyroid cancer (Shindo 2017, Lovejoy 2018, Yehia 2018). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH6 Met492Val as a variant of uncertain significance due to insufficient evidence for classification (Thompson 2014). MSH6 Met492Val was observed at an allele frequency of 0.04% (11/25,786) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located within the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Met492Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115374 SCV000185429 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing The p.M492V variant (also known as c.1474A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1474. The methionine at codon 492 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in multiple individuals, including one family from the Danish HNPCC-registry (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83), one family meeting Amsterdam criteria (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100), two unrelated individuals from HNPCC families with colon tumors demonstrating normal MSH6 expression on IHC studies (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7), and a patient diagnosed with a pancreatic neuroendocrine tumor at age 57 (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). In addition, one functional study reported this variant to be proficient in in vitro mismatch repair (MMR) activity (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000524111 SCV000260884 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 492 of the MSH6 protein (p.Met492Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs61754783, ExAC 0.05%). This variant has been reported in individuals from families with suspected Lynch syndrome (PMID: 12658575, 22495361, 18566915), an individual affected with ovarian cancer (PMID: 23047549), and an individual with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 89195). Experimental studies have shown that this missense change does not affect MSH6 mismatch repair activity in an in vitro assay (PMID: 22102614). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587662 SCV000695784 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1474A>G (p.Met492Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/121326 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported in the literature in patients/families with suspected Lynch Syndrome (Nilbert_2009, Okkels_2012, Wagner_2003) and ovarian cancer (Pal_2012), without strong evidence for causality (lacking co-segregation data). Despite its presence in affected individuals, an in vitro assay showed the variant to have similar MMR activity compared to WT (Drost_2011). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212649 SCV000712331 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing The p.Met492Val variant in MSH6 has been reported in 4 individuals with Lynch sy ndrome-related cancers (Wagner 2003, Okkels 2012, Pal 2012). In vitro functional studies provide some evidence that the p.Met492Val variant may not impact prote in function (Drost 2012). However, these types of assays may not accurately repr esent biological function. This variant has been identified in 3/6610 Finnish ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs61754783). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addit ion, this variant was classified as a Variant of Uncertain Significance on Sep 5 , 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107859.2). In summary, the clinical significance of the p.Met492Val variant is uncertain.
PreventionGenetics,PreventionGenetics RCV000587662 SCV000805844 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115374 SCV000902794 likely benign Hereditary cancer-predisposing syndrome 2016-03-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353728 SCV000592585 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Met492Val variant was identified in 2 of 2234 proband chromosomes (frequency: 0.001) from families with Lynch syndrome (Nilbert 2009, Wagner 2003); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs61754783) “With Uncertain significance allele”, HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, ClinVar database (classified as having uncertain significance by the InSiGHT expert review panel), and UMD (1X as an unclassified variant). An in vitro functional study by Drost (2011) demonstrated that the variant had similar mismatch repair efficiency to wild type MSH6, and an in silico study analyzing structural properties suggests that the variant has no impact on the MSH6 protein (Terui 2013).The p.Met492 residue is conserved in mammals but not across all lower organisms, 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. 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 unknown significance.

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