ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1929G>T (p.Gln643His) (rs786203379)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166658 SCV000217463 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000218174 SCV000279816 uncertain significance not provided 2018-03-28 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1929G>T at the cDNA level, p.Gln643His (Q643H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located within the MLH1 interaction domain (Kondo 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Gln643His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000549602 SCV000625567 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 643 of the PMS2 protein (p.Gln643His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186985). 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, this variant has uncertain impact on PMS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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