ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2347T>A (p.Cys783Ser) (rs373721483)

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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 RCV000222377 SCV000277505 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000465704 SCV000551249 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 783 of the MSH6 protein (p.Cys783Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs373721483, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233180). 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. However, an algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Mendelics RCV000708874 SCV000837895 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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