ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1846C>T (p.Arg616Cys)

gnomAD frequency: 0.00001  dbSNP: rs752076074
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001560773 SCV000653090 uncertain significance not provided 2024-12-22 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 616 of the POLE protein (p.Arg616Cys). This variant is present in population databases (rs752076074, 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: 473491). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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 RCV001560773 SCV001783246 uncertain significance not provided 2023-09-26 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
Mendelics RCV002248778 SCV002519183 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002248778 SCV002550170 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002413620 SCV002715129 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-23 criteria provided, single submitter clinical testing The p.R616C variant (also known as c.1846C>T), located in coding exon 17 of the POLE gene, results from a C to T substitution at nucleotide position 1846. The arginine at codon 616 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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