ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.632G>A (p.Arg211Gln) (rs587781934)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130297 SCV000185146 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212846 SCV000211570 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.632G>A at the cDNA level, p.Arg211Gln (R211Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been reported in at least one patient with ovarian cancer undergoing multigene panel testing (Kraus 2017). PMS2 Arg211Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg211Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200665 SCV000254617 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 211 of the PMS2 protein (p.Arg211Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587781934, ExAC 0.001%). This variant has been reported in an individual affected with ovarian cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 141683). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000412393 SCV000487980 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2015-12-09 criteria provided, single submitter clinical testing
Color RCV000130297 SCV000686223 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212846 SCV000889635 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781748 SCV000920037 uncertain significance not specified 2017-09-13 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.632G>A (p.Arg211Gln) variant causes a missense change involving the alteration of a conserved nucleotide located in the Ribosomal protein S5 domain 2-type fold (IPR020568) (InterPro). 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). This variant has been reported and classified as a VUS in one ovarian cancer patient without strong evidence for or against pathogenicity (Kraus_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

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