ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.950A>G (p.Gln317Arg)

dbSNP: rs537024768
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699865 SCV000828595 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 317 of the PMS2 protein (p.Gln317Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 577182). 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 disruptive. 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.
Genetic Services Laboratory, University of Chicago RCV001816727 SCV002072016 uncertain significance not specified 2021-09-23 criteria provided, single submitter clinical testing DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.950A>G, in exon 9 that results in an amino acid change, p.Gln317Arg. This sequence change has not been described in population databases including ExAC and gnomAD (dbSNP rs537024768). The p.Gln317Arg change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Gln317Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with PMS2-related disorders, however a truncating variant at this position has been reported in an individual with early-age onset colorectal cancer and whose tumor showed loss of PMS2 by immunohistochemistry (PMID: 186029220). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gln317Arg change remains unknown at this time.
Ambry Genetics RCV002369915 SCV002686002 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-17 criteria provided, single submitter clinical testing The p.Q317R variant (also known as c.950A>G), located in coding exon 9 of the PMS2 gene, results from an A to G substitution at nucleotide position 950. The glutamine at codon 317 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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