ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5566T>C (p.Phe1856Leu)

gnomAD frequency: 0.00002  dbSNP: rs1060500846
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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 RCV001558887 SCV000544106 uncertain significance not provided 2024-07-17 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1856 of the POLE protein (p.Phe1856Leu). This variant is present in population databases (no rsID available, 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: 405785). 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.
GeneDx RCV001558887 SCV001780922 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002348284 SCV002653148 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-14 criteria provided, single submitter clinical testing The p.F1856L variant (also known as c.5566T>C), located in coding exon 41 of the POLE gene, results from a T to C substitution at nucleotide position 5566. The phenylalanine at codon 1856 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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