ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2377C>G (p.Gln793Glu) (rs730881769)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656881 SCV000211208 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2377C>G at the cDNA level, p.Gln793Glu (Q793E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln793Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in 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 Gln793Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160611 SCV000215815 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000542071 SCV000625376 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 793 of the MSH2 protein (p.Gln793Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182579). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212618 SCV000731360 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing The p.Gln793Glu variant in MSH2 has not been previously reported in individuals with Lynch syndrome or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Gln793Glu variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. In summary, the clinical significance of the p.Gln793Glu variant is un certain.
Color RCV000160611 SCV000903226 likely benign Hereditary cancer-predisposing syndrome 2016-02-26 criteria provided, single submitter clinical testing

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