ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1129G>A (p.Ala377Thr)

dbSNP: rs754508108
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564313 SCV000671581 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-03 criteria provided, single submitter clinical testing The p.A377T variant (also known as c.1129G>A), located in coding exon 12 of the POLE gene, results from a G to A substitution at nucleotide position 1129. The alanine at codon 377 is replaced by threonine, an amino acid with similar properties. 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 this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001662619 SCV000961813 uncertain significance not provided 2025-01-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 377 of the POLE protein (p.Ala377Thr). This variant is present in population databases (rs754508108, gnomAD 0.007%). 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: 484514). 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 RCV001662619 SCV001872614 uncertain significance not provided 2021-07-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); 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: 20951805)
Sema4, Sema4 RCV000564313 SCV002538591 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-21 criteria provided, single submitter curation
Baylor Genetics RCV004569241 SCV005056543 uncertain significance Colorectal cancer, susceptibility to, 12 2024-02-27 criteria provided, single submitter clinical testing

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