ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2596A>G (p.Lys866Glu)

dbSNP: rs1553413941
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568107 SCV000662569 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-20 criteria provided, single submitter clinical testing The p.K866E variant (also known as c.2596A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2596. The lysine at codon 866 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.002 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000629749 SCV000750705 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-09-29 criteria provided, single submitter clinical testing 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. 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"). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 866 of the MSH6 protein (p.Lys866Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid.
All of Us Research Program, National Institutes of Health RCV004000887 SCV004817264 uncertain significance Lynch syndrome 2023-02-24 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 866 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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