ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1396A>G (p.Thr466Ala)

gnomAD frequency: 0.00001  dbSNP: rs761765763
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001011321 SCV001171627 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-15 criteria provided, single submitter clinical testing The p.T466A variant (also known as c.1396A>G), located in coding exon 14 of the POLE gene, results from an A to G substitution at nucleotide position 1396. The threonine at codon 466 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001868290 SCV002108988 uncertain significance Colorectal cancer, susceptibility to, 12 2022-10-07 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 466 of the POLE protein (p.Thr466Ala). This variant is present in population databases (rs761765763, gnomAD 0.01%). 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: 560020). 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 expected to disrupt POLE protein function. 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.
Baylor Genetics RCV001868290 SCV004203548 uncertain significance Colorectal cancer, susceptibility to, 12 2023-08-01 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677898 SCV000804059 uncertain significance Colon cancer 2017-06-15 no assertion criteria provided clinical testing

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