ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2284C>T (p.Arg762Trp)

gnomAD frequency: 0.00001  dbSNP: rs1064794759
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484240 SCV000569891 uncertain significance not provided 2022-06-13 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; Published functional study demonstrates no damaging effect on mutation rate (Barbari 2018); Observed in an individual with hepatocellular carcinoma (Ang 2019); This variant is associated with the following publications: (PMID: 23263490, 22810696, 29352080, 31258846)
Labcorp Genetics (formerly Invitae), Labcorp RCV000484240 SCV001223981 uncertain significance not provided 2024-09-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 762 of the POLE protein (p.Arg762Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 420873). 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 expected to disrupt POLE protein function with a positive 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.

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