ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1382A>C (p.Asp461Ala) (rs730881756)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160583 SCV000211176 uncertain significance not provided 2018-03-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1382A>C at the cDNA level, p.Asp461Ala (D461A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp461Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Clamp domain and the region that interacts with MSH6 and MSH3 (Guerrette 1998, L?tzen 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 Asp461Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198641 SCV000254384 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 461 of the MSH2 protein (p.Asp461Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs730881756, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182558). 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.
Ambry Genetics RCV000492025 SCV000580622 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000492025 SCV000684934 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
Counsyl RCV000662679 SCV000785387 uncertain significance Lynch syndrome I 2017-07-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160583 SCV000889412 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing

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