ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2270A>G (p.Tyr757Cys) (rs780448421)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690793 SCV000818520 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 757 of the MSH2 protein (p.Tyr757Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. 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. 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.
Ambry Genetics RCV001015003 SCV001175786 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-30 criteria provided, single submitter clinical testing The p.Y757C variant (also known as c.2270A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2270. The tyrosine at codon 757 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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