ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.824A>G (p.Gln275Arg) (rs546966892)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212852 SCV000149614 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.824A>G at the cDNA level, p.Gln275Arg (Q275R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Gln275Arg was not observed at significant allele frequency in large population cohorts (Lek 2016). PMS2 Gln275Arg is located in the ATPase domain (Guarne 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 Gln275Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115705 SCV000217858 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000533498 SCV000625696 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 275 of the PMS2 protein (p.Gln275Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs546966892, ExAC 0.03%). 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: 127797). 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 arginine 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 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.
Color RCV000115705 SCV000909670 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing

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