ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.847A>C (p.Ser283Arg) (rs876660871)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220531 SCV000278649 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000767166 SCV000279719 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.847A>C at the cDNA level, p.Ser283Arg (S283R) at the protein level, and results in the change of a Serine to an Arginine (AGT>CGT). This variant has been observed in at least one individual with a personal history of Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). PMS2 Ser283Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Ser283Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000767166 SCV000601862 uncertain significance not provided 2019-05-24 criteria provided, single submitter clinical testing
Invitae RCV000545236 SCV000625700 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-06 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 283 of the PMS2 protein (p.Ser283Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in one individual undergoing Lynch syndrome genetic testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 234135). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Color RCV000220531 SCV000686245 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing

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