ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.565G>A (p.Ala189Thr) (rs63750821)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236727 SCV000292618 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.565G>A at the cDNA level, p.Ala189Thr (A189T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ala189Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ala189Thr is located in the connector domain (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 Ala189Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000691636 SCV000819422 uncertain significance Hereditary nonpolyposis colon cancer 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 189 of the MSH2 protein (p.Ala189Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs63750821, 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: 245646). 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: "Benign"; 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236727 SCV000888223 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing

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