ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6196A>G (p.Ile2066Val)

gnomAD frequency: 0.00001  dbSNP: rs1266801207
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003541120 SCV001215224 uncertain significance not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2066 of the POLE protein (p.Ile2066Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 847525). 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.
Mendelics RCV002249657 SCV002519161 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002355034 SCV002655037 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-28 criteria provided, single submitter clinical testing The p.I2066V variant (also known as c.6196A>G), located in coding exon 45 of the POLE gene, results from an A to G substitution at nucleotide position 6196. The isoleucine at codon 2066 is replaced by valine, 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.

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