ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3229C>T (p.Arg1077Cys)

gnomAD frequency: 0.00009  dbSNP: rs149777592
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000481822 SCV000543903 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 1077 of the POLE protein (p.Arg1077Cys). This variant is present in population databases (rs149777592, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 405597). 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 RCV000481822 SCV000569982 uncertain significance not provided 2024-10-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal and other cancers (PMID: 26580448, 28873162, 29212164); This variant is associated with the following publications: (PMID: 26580448, 25194279, 28166811, 28873162, 29212164, 29338072)
Ambry Genetics RCV000572529 SCV000671334 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-10 criteria provided, single submitter clinical testing The p.R1077C variant (also known as c.3229C>T), located in coding exon 26 of the POLE gene, results from a C to T substitution at nucleotide position 3229. The arginine at codon 1077 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481822 SCV001469624 uncertain significance not provided 2019-12-10 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000481822 SCV005192066 uncertain significance not provided criteria provided, single submitter not provided
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV004787711 SCV005402246 uncertain significance Colorectal cancer, susceptibility to, 12 2024-03-04 criteria provided, single submitter clinical testing The POLE c.3229C>T (p.Arg1077Cys) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. The variant is not located within the exonuclease domain. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000481822 SCV005408431 uncertain significance not provided 2024-05-21 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000572529 SCV005688930 uncertain significance Hereditary cancer-predisposing syndrome 2025-01-15 criteria provided, single submitter clinical testing The missense variant NM_006231.4(POLE):c.3229C>T (p.Arg1077Cys) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.The p.Arg1077Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 1077 of POLE is conserved in all mammalian species. The nucleotide c.3229 in POLE is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance

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