ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1703C>G (p.Pro568Arg) (rs869312801)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210189 SCV000266217 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000217199 SCV000276656 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524444 SCV000552026 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 568 of the PMS2 protein (p.Pro568Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with primary peritoneal cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224585). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000479827 SCV000568115 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1703C>G at the cDNA level, p.Pro568Arg (P568R) at the protein level, and results in the change of a Proline to an Arginine (CCA>CGA). This variant was identified via multigene cancer panel testing in an individual with a personal history of primary peritoneal cancer and family history of breast and pancreatic cancer (Shirts 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). Since Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Pro568Arg is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Pro568Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217199 SCV000903281 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-04 criteria provided, single submitter clinical testing

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