ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1618G>A (p.Val540Ile)

gnomAD frequency: 0.00002  dbSNP: rs770307281
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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 RCV002464150 SCV000289262 uncertain significance not provided 2024-10-20 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 540 of the POLE protein (p.Val540Ile). This variant is present in population databases (rs770307281, gnomAD 0.02%). 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: 240399). 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.
Ambry Genetics RCV002401898 SCV002708005 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-29 criteria provided, single submitter clinical testing The p.V540I variant (also known as c.1618G>A), located in coding exon 15 of the POLE gene, results from a G to A substitution at nucleotide position 1618. The valine at codon 540 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV002464150 SCV002759281 uncertain significance not provided 2022-11-30 criteria provided, single submitter clinical testing 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; This variant is associated with the following publications: (PMID: 20951805)

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