ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1780A>G (p.Thr594Ala)

gnomAD frequency: 0.00009  dbSNP: rs762067222
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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 RCV001662586 SCV000653082 uncertain significance not provided 2025-01-05 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 594 of the POLE protein (p.Thr594Ala). This variant is present in population databases (rs762067222, gnomAD 0.008%). 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: 473483). 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 RCV000564861 SCV000671424 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing The p.T594A variant (also known as c.1780A>G), located in coding exon 16 of the POLE gene, results from an A to G substitution at nucleotide position 1780. The threonine at codon 594 is replaced by alanine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. 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 p.T594A remains unclear.
GeneDx RCV001662586 SCV001872835 uncertain significance not provided 2023-10-16 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; 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

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