ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6475C>T (p.Arg2159Cys)

gnomAD frequency: 0.00001  dbSNP: rs5745067
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000605020 SCV000712977 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing The p.Arg2159Cys variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/51720 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs5745067). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Arg2159Cys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV001584422 SCV000826545 uncertain significance not provided 2025-01-02 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 2159 of the POLE protein (p.Arg2159Cys). This variant is present in population databases (rs5745067, gnomAD 0.006%). 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: 505637). 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.
GeneDx RCV001584422 SCV001812854 uncertain significance not provided 2024-03-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19296856)
CeGaT Center for Human Genetics Tuebingen RCV001584422 SCV004136738 likely benign not provided 2022-08-01 criteria provided, single submitter clinical testing POLE: BP4
Fulgent Genetics, Fulgent Genetics RCV005010590 SCV005634220 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-06-19 criteria provided, single submitter clinical testing

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