ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6493C>T (p.Arg2165Cys)

gnomAD frequency: 0.00002  dbSNP: rs369549727
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002253313 SCV000289461 uncertain significance not provided 2025-01-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2165 of the POLE protein (p.Arg2165Cys). This variant is present in population databases (rs369549727, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 240597). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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, Mass General Brigham 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 (http://gnomad.broadinstitute.org; 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.
GeneDx RCV002253313 SCV002525362 uncertain significance not provided 2023-12-01 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19296856)

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