ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3560A>G (p.Glu1187Gly) (rs150632241)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464152 SCV000551220 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1187 of the MSH6 protein (p.Glu1187Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs150632241, ExAC 0.002%) but has not been reported in the literature in individuals with a MSH6-related disease. General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be disruptive. However, these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on 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.
GeneDx RCV000486385 SCV000568927 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3560A>G at the cDNA level, p.Glu1187Gly (E1187G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu1187Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Glu1187Gly is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Glu1187Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491973 SCV000580244 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000491973 SCV000690375 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing

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