ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2465A>G (p.Lys822Arg)

dbSNP: rs986217332
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003656351 SCV001224464 uncertain significance not provided 2023-11-21 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 822 of the POLE protein (p.Lys822Arg). This variant is not present in population databases (gnomAD no frequency). 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: 854713). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Ambry Genetics RCV002451252 SCV002736076 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-10 criteria provided, single submitter clinical testing The p.K822R variant (also known as c.2465A>G), located in coding exon 21 of the POLE gene, results from an A to G substitution at nucleotide position 2465. The lysine at codon 822 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003396697 SCV004120857 uncertain significance POLE-related condition 2022-08-31 criteria provided, single submitter clinical testing The POLE c.2465A>G variant is predicted to result in the amino acid substitution p.Lys822Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133241891-T-C). This variant is listed in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/854713/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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