ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2041C>G (p.Gln681Glu) (rs730881762)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160598 SCV000211194 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2041C>G at the cDNA level, p.Gln681Glu (Q681E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln681Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (L?tzen 2008, Kansikas 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 MSH2 Gln681Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000203996 SCV000261679 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 681 of the MSH2 protein (p.Gln681Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182568). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001014194 SCV001174876 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing Insufficient evidence

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