ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1831G>A (p.Val611Met) (rs369385048)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232146 SCV000284124 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 611 of the MSH2 protein (p.Val611Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs369385048, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237376). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000481079 SCV000567929 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1831G>A at the cDNA level, p.Val611Met (V611M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val611Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val611Met is located in the Lever domain and the region of interaction with MSH6, MSH3, and EXO1 (Guerrette 1998, L?tzen 2008, 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 MSH2 Val611Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575973 SCV000662227 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000575973 SCV000684982 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
Counsyl RCV000662772 SCV000785573 uncertain significance Lynch syndrome I 2017-09-22 criteria provided, single submitter clinical testing
GeneKor MSA RCV000575973 SCV000822050 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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