ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4410G>A (p.Met1470Ile)

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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 RCV003683061 SCV004408116 uncertain significance not provided 2023-04-07 criteria provided, single submitter clinical testing 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. 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. This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1470 of the POLE protein (p.Met1470Ile).
Ambry Genetics RCV004661717 SCV005154318 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-21 criteria provided, single submitter clinical testing The p.M1470I variant (also known as c.4410G>A), located in coding exon 34 of the POLE gene, results from a G to A substitution at nucleotide position 4410. The methionine at codon 1470 is replaced by isoleucine, 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. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx RCV003683061 SCV005387287 uncertain significance not provided 2024-02-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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