ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2156A>G (p.Gln719Arg) (rs587782559)

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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 RCV000131777 SCV000186824 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing The p.Q719R variant (also known as c.2156A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2156. The glutamine at codon 719 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000662647 SCV000785334 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
Invitae RCV000802314 SCV000942139 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 719 of the PMS2 protein (p.Gln719Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. 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: 142576). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV001175084 SCV001338650 uncertain significance not specified 2020-04-20 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2156A>G (p.Gln719Arg) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 236580 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2156A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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