ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2363C>T (p.Ala788Val)

gnomAD frequency: 0.00002  dbSNP: rs1060500813
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000759987 SCV000544004 uncertain significance not provided 2025-02-01 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 788 of the POLE protein (p.Ala788Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 405689). 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 RCV000759987 SCV000889725 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV002446785 SCV002735115 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-26 criteria provided, single submitter clinical testing The p.A788V variant (also known as c.2363C>T), located in coding exon 21 of the POLE gene, results from a C to T substitution at nucleotide position 2363. The alanine at codon 788 is replaced by valine, an amino acid with 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 RCV000759987 SCV005385022 uncertain significance not provided 2024-02-21 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with melanoma and family history of melanoma, colorectal cancer and gastric cancer (PMID: 34326862); This variant is associated with the following publications: (PMID: 20951805, 34326862)

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