ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.6493C>T (p.Arg2165Cys) (rs369549727)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227104 SCV000289461 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2165 of the POLE protein (p.Arg2165Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs369549727, ExAC 0.02%). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 240597). 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 C0"). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826022 SCV000967511 uncertain significance not specified 2018-08-22 criteria provided, single submitter clinical testing The p.Arg2165Cys variant in POLE has not been previously reported in the literat ure in individuals with colorectal cancer but has been reported by other clinica l laboratories in ClinVar (Variation ID 240597). It has also been identified in 1/18498 East Asian chromosomes by gnomAD (; dbSN P rs369549727). Computational prediction tools and conservation analysis suggest that the p.Arg2165Cys variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical sig nificance of the p.Arg2165Cys variant is uncertain. ACMG/AMP Criteria applied: P P3, PM2.

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