ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.682G>A (p.Glu228Lys) (rs587779947)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115441 SCV000149350 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.682G>A at the cDNA level, p.Glu228Lys (E228K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Glu228Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signals (Gassman 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 Glu228Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410116 SCV000488711 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-05-26 criteria provided, single submitter clinical testing
Invitae RCV000466432 SCV000551269 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 228 of the MSH6 protein (p.Glu228Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs587779947, ExAC 0.002%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127604). 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000566072 SCV000662437 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000566072 SCV000690470 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing

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