ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3356A>G (p.Glu1119Gly) (rs876661138)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216765 SCV000279647 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3356A>G at the cDNA level, p.Glu1119Gly (E1119G) 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 Glu1119Gly was not observed 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 Glu1119Gly is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Glu1119Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491795 SCV000580364 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000536220 SCV000624850 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1119 of the MSH6 protein (p.Glu1119Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234647). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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