ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2438G>T (p.Arg813Leu) (rs587782665)

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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 RCV000132085 SCV000187149 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-17 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000231154 SCV000285120 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 813 of the PMS2 protein (p.Arg813Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. 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 been observed in individuals affected with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 142715). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000478307 SCV000567940 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2438G>T at the cDNA level, p.Arg813Leu (R813L) at the protein level, and results in the change of an Arginine to a Leucine (CGG>CTG). This variant has been observed in two individuals presenting with early onset colorectal cancer; both individuals? tumors were reported to be PMS2 proficient (Pearlman 2017). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology. This variant is located in Endonuclease domain and the Zinc binding conserved motif (Kosinski 2008, 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 Arg813Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478307 SCV001134595 uncertain significance not provided 2019-03-25 criteria provided, single submitter clinical testing

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