ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.797G>T (p.Arg266Leu)

gnomAD frequency: 0.00001  dbSNP: rs115786159
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003766503 SCV000544061 uncertain significance not provided 2024-09-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 266 of the POLE protein (p.Arg266Leu). This variant is present in population databases (rs115786159, 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: 405740). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000615370 SCV000712699 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing The p.Arg266Leu variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 4/66730 of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs115786159). Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Arg266Leu variant is uncertain.
Genetic Services Laboratory, University of Chicago RCV000615370 SCV002071925 uncertain significance not specified 2021-10-14 criteria provided, single submitter clinical testing DNA sequence analysis of the POLE gene demonstrated a sequence change, c.797G>T, in exon 8 that results in an amino acid change, p.Arg266Leu. This sequence change does not appear to have been previously described in individuals with POLE-related disorders. This sequence change has been described in four non-Finnish European individuals in the gnomAD population database (dbSNP rs115786159). The p.Arg266Leu change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg266Leu substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg266Leu change remains unknown at this time.
Ambry Genetics RCV002418362 SCV002681643 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-09 criteria provided, single submitter clinical testing The p.R266L variant (also known as c.797G>T), located in coding exon 8 of the POLE gene, results from a G to T substitution at nucleotide position 797. The arginine at codon 266 is replaced by leucine, an amino acid with 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000615370 SCV002760988 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
GeneDx RCV003766503 SCV005079092 uncertain significance not provided 2024-04-04 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

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