ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2185C>G (p.Leu729Val) (rs1554294503)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000531598 SCV000625596 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 729 of the PMS2 protein (p.Leu729Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 455690). 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000586740 SCV000697338 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2185C>G (p.Leu729Val) variant involves the alteration of a conserved nucleotide. Leu729 is highly conserved across species and is located in the MutL, C-terminal, dimerisation domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was absent in 81156 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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