ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4046C>T (p.Ala1349Val)

gnomAD frequency: 0.00001  dbSNP: rs536988344
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000760011 SCV000544230 uncertain significance not provided 2024-12-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1349 of the POLE protein (p.Ala1349Val). This variant is present in population databases (rs536988344, gnomAD 0.006%). 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: 405902). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760011 SCV000889752 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000760011 SCV001769468 uncertain significance not provided 2023-09-21 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; This variant is associated with the following publications: (PMID: 28912153, 35506567)
Ambry Genetics RCV003168761 SCV003897547 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-11 criteria provided, single submitter clinical testing The p.A1349V variant (also known as c.4046C>T), located in coding exon 32 of the POLE gene, results from a C to T substitution at nucleotide position 4046. The alanine at codon 1349 is replaced by valine, an amino acid with 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000468394 SCV003928140 uncertain significance Colorectal cancer, susceptibility to, 12 2023-05-03 criteria provided, single submitter clinical testing The POLE c.4046C>T (p.Ala1349Val) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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