ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1339A>C (p.Met447Leu)

dbSNP: rs376095661
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003654931 SCV000653047 uncertain significance not provided 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 447 of the POLE protein (p.Met447Leu). This variant is present in population databases (rs376095661, gnomAD 0.0009%). 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: 473451). 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 RCV000571348 SCV000676232 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-29 criteria provided, single submitter clinical testing The p.M447L variant (also known as c.1339A>C), located in coding exon 13 of the POLE gene, results from an A to C substitution at nucleotide position 1339. The methionine at codon 447 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
Baylor Genetics RCV004569068 SCV005056557 uncertain significance Colorectal cancer, susceptibility to, 12 2023-11-14 criteria provided, single submitter clinical testing

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