ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2519T>C (p.Val840Ala) (rs1064794561)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482567 SCV000569441 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2519T>C at the cDNA level, p.Val840Ala (V840A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Val840Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Val840Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568796 SCV000669716 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000630056 SCV000751012 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 840 of the MSH2 protein (p.Val840Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 420561). 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, 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.

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