ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3883C>A (p.Leu1295Met)

gnomAD frequency: 0.00001  dbSNP: rs1184724406
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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 RCV001561797 SCV000653246 uncertain significance not provided 2025-02-03 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1295 of the POLE protein (p.Leu1295Met). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 473629). 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.
GeneDx RCV001561797 SCV001784459 uncertain significance not provided 2023-01-25 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
Ambry Genetics RCV004024245 SCV003733532 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-28 criteria provided, single submitter clinical testing The c.3883C>A (p.L1295M) alteration is located in exon 31 (coding exon 31) of the POLE gene. This alteration results from a C to A substitution at nucleotide position 3883, causing the leucine (L) at amino acid position 1295 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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