ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.763G>T (p.Gly255Cys) (rs1555685930)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568236 SCV000671977 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000540866 SCV000632804 uncertain significance Juvenile polyposis syndrome 2017-01-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 255 of the SMAD4 protein (p.Gly255Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD4-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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel 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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