ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1463C>T (p.Ala488Val) (rs587779328)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221900 SCV000273766 likely benign Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000076811 SCV000296931 uncertain significance Lynch syndrome 2015-10-12 criteria provided, single submitter clinical testing
Invitae RCV000684795 SCV000552061 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 488 of the PMS2 protein (p.Ala488Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs587779328, ExAC 0.01%). This variant has been reported in an individual with suspected hereditary cancer (PMID: 27435373). ClinVar contains an entry for this variant (Variation ID: 91303). Experimental studies have shown that this missense change does not disrupt mismatch repair activity (PMID: 27435373). 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.
GeneDx RCV000657046 SCV000567509 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1463C>T at the cDNA level, p.Ala488Val (A488V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been observed in at least one individual with adenomatous colorectal polyps, but demonstrated proficient mismatch repair (MMR) activity in an in vitro MMR assay (van der Klift 2016). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant 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 Ala488Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483082 SCV000601818 likely benign not specified 2017-03-30 criteria provided, single submitter clinical testing
Color RCV000221900 SCV000903597 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing

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