ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1796A>T (p.Asp599Val) (rs878854039)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232833 SCV000285089 uncertain significance Lynch syndrome 2016-01-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 599 of the PMS2 protein (p.Asp599Val). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. While 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, algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter splicing through the creation of a cryptic splice site. These predictions have not been confirmed by published functional studies. In summary, this is a novel missense change that is not predicted to affect protein function, but is predicted to affect mRNA splicing. 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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