ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2292G>C (p.Trp764Cys) (rs63751105)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000684788 SCV000548252 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 764 of the MSH2 protein (p.Trp764Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant occurs with a pathogenic deletion of MSH2 exons 8-10 in individuals affected with Lynch syndrome in the literature (PMID: 18987546) and in the Leiden Open-source Variation (LOVD) Database (PMID: 21520333). While it is unknown if these variants are on the same or opposite chromosomes in two of these individuals, this variant is reported to occur in cis with the MSH2 exon 8-10 deletion in one individual in the LOVD database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 90950). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000491833 SCV000580404 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing Conflicting evidence

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