ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2537A>G (p.Gln846Arg) (rs140754514)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656883 SCV000211219 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2537A>G at the cDNA level, p.Gln846Arg (Q846R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Gln846Arg 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 Gln846Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160621 SCV000215957 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168241 SCV000218911 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 846 of the MSH2 protein (p.Gln846Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs140754514, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182585). 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000160621 SCV000685052 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235176 SCV000712847 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Gln846Arg variant in MSH2 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 3/10406 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs140754514). Computational prediction tools and conservation analysis suggest that the p.Gln846Arg variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Gln846Arg variant is uncertain.
Counsyl RCV000663089 SCV000786184 uncertain significance Lynch syndrome I 2018-03-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656883 SCV000806031 uncertain significance not provided 2017-10-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656883 SCV000889429 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000235176 SCV000691912 uncertain significance not specified no assertion criteria provided clinical testing

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