ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4453C>T (p.Arg1485Cys)

gnomAD frequency: 0.00001  dbSNP: rs969429633
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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 RCV001571326 SCV000653289 uncertain significance not provided 2024-12-24 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 1485 of the POLE protein (p.Arg1485Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 473665). 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 RCV001571326 SCV001795776 uncertain significance not provided 2019-05-03 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004944000 SCV005478860 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-09 criteria provided, single submitter clinical testing The p.R1485C variant (also known as c.4453C>T), located in coding exon 35 of the POLE gene, results from a C to T substitution at nucleotide position 4453. The arginine at codon 1485 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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