ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3778G>A (p.Ala1260Thr)

gnomAD frequency: 0.00004  dbSNP: rs143858927
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000760007 SCV000289342 uncertain significance not provided 2025-01-22 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 1260 of the POLE protein (p.Ala1260Thr). This variant is present in population databases (rs143858927, gnomAD 0.006%). 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: 240478). 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 RCV000760007 SCV000889748 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000760007 SCV001871172 uncertain significance not provided 2024-04-05 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002347894 SCV002623515 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-27 criteria provided, single submitter clinical testing The p.A1260T variant (also known as c.3778G>A), located in coding exon 30 of the POLE gene, results from a G to A substitution at nucleotide position 3778. The alanine at codon 1260 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs143858927. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. This amino acid position is not 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.A1260T remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005003578 SCV005633719 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-03-09 criteria provided, single submitter clinical testing

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