ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1169C>T (p.Ala390Val) (rs587780039)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115651 SCV000184320 likely benign Hereditary cancer-predisposing syndrome 2018-03-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000115651 SCV000904176 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000212859 SCV000149560 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1169C>T at the cDNA level, p.Ala390Val (A390V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been reported in at least one individual with endometrial cancer (Castellanos 2017). 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). PMS2 Ala390Val is not located in a known functional domain. 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 Ala390Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229947 SCV000285048 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 390 of the PMS2 protein (p.Ala390Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant (rs587780039) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in the literature in an individual affected with endometrial cancer (PMID: 28051113). ClinVar contains an entry for this variant (Variation ID: 127754). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional 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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