ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3220A>G (p.Met1074Val) (rs730881804)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587626 SCV000211315 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3220A>G at the cDNA level, p.Met1074Val (M1074V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in an individual with suspected Hereditary Nonpolyposis Colorectal Cancer whose tumor demonstrated decreased, but not absent, MSH6 expression on immunohistochemistry (Okkels 2012). MSH6 Met1074Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the lever domain (Warren 2007, 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 MSH6 Met1074Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232219 SCV000283792 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1074 of the MSH6 protein (p.Met1074Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs730881804, ExAC 0.001%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 22495361). ClinVar contains an entry for this variant (Variation ID: 182645). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000562784 SCV000662419 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000562784 SCV000690331 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587626 SCV000695844 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3220A>G (p.Met1074Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome, and Met1074 is located in the core domain of the DNA mismatch repair protein Msh6. This variant was found in 1/121320 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, one clinical diagnostic laboratory classified this variant as a VUS. The variant was identified in one patient with a colon adenocarcinoma and suspected HNPCC, and shown to have reduced MSH6 expression via immunohistochemistry; however, no data was provided to conclusively prove causality (Okkels_Appl Immunohistochem Mol Morphol_2012). Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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