ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2207A>T (p.Glu736Val) (rs1060503115)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475054 SCV000552046 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 736 of the PMS2 protein (p.Glu736Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. A variant with the same transcript coordinates at this variant (c.2207A>T) has been reported in the literature in a family affected with Lynch syndrome that also had a pathogenic p.Leu731* variant on the same PMS2 allele (PMID: 25430799). However, the description of the protein effect for this c.2207A>T variant is discordant, making it unclear if this is truly the same variant. It was also not clearly determined whether the variant occurred in PMS2 or a PMS2-pseudogene in that individual. ClinVar contains an entry for this variant (Variation ID: 411073). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, 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.

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