ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2473C>T (p.Arg825Cys)

gnomAD frequency: 0.00002  dbSNP: rs200283666
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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 RCV002281110 SCV000653137 uncertain significance not provided 2025-02-03 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 825 of the POLE protein (p.Arg825Cys). This variant is present in population databases (rs200283666, gnomAD 0.004%). 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: 473532). 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.
GeneDx RCV002281110 SCV002569844 uncertain significance not provided 2023-11-21 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: 20951805)
Ambry Genetics RCV002456234 SCV002737468 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-09 criteria provided, single submitter clinical testing The p.R825C variant (also known as c.2473C>T), located in coding exon 22 of the POLE gene, results from a C to T substitution at nucleotide position 2473. The arginine at codon 825 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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