ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1282A>G (p.Lys428Glu)

dbSNP: rs761822293
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000538584 SCV000624634 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-01-18 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 428 of the MSH6 protein (p.Lys428Glu). This variant is present in population databases (rs761822293, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28195393, 31297992). ClinVar contains an entry for this variant (Variation ID: 455128). 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 disruptive. 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 RCV000567668 SCV000662523 pathogenic Hereditary cancer-predisposing syndrome 2022-06-10 criteria provided, single submitter clinical testing The p.K428E pathogenic mutation (also known as c.1282A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1282. The lysine at codon 428 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been identified in an individual diagnosed with colorectal cancer at 41 (Hansen MF et al. Clin Genet, 2017 Oct;92:405-414). This mutation was also found and in multiple probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability (MSI-H) and/or isolated loss of MSH6 staining on immunohistochemistry, at least one of whom met Amsterdam criteria (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV000567668 SCV000908372 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-29 criteria provided, single submitter clinical testing

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