ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1945G>A (p.Ala649Thr) (rs786201822)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164307 SCV000214938 likely benign Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Color RCV000164307 SCV000690033 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing
Invitae RCV001059239 SCV001223859 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 649 of the MSH2 protein (p.Ala649Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 184961). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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