ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1423G>A (p.Val475Met) (rs864622579)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205763 SCV000261190 uncertain significance Lynch syndrome 2015-10-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 475 of the PMS2 protein (p.Val475Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. 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. Additionally, the methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.

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