ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2062A>T (p.Ile688Leu) (rs1060503144)

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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 RCV000569372 SCV000663533 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-26 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000630098 SCV000751054 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 688 of the PMS2 protein (p.Ile688Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. 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. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 480350). 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 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.

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