ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1631T>C (p.Ile544Thr) (rs587778524)

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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 RCV000569681 SCV000662223 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
ITMI RCV000121560 SCV000085754 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000472209 SCV000548169 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 544 of the MSH2 protein (p.Ile544Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587778524, ExAC 0.001%) but has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 134842). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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