ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6734C>G (p.Thr2245Ser)

gnomAD frequency: 0.00001  dbSNP: rs747676884
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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 RCV000759320 SCV000653456 uncertain significance not provided 2025-01-07 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 2245 of the POLE protein (p.Thr2245Ser). This variant is present in population databases (rs747676884, 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: 473811). 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 RCV000759320 SCV000888575 uncertain significance not provided 2020-01-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV002377155 SCV002667408 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-16 criteria provided, single submitter clinical testing The p.T2245S variant (also known as c.6734C>G), located in coding exon 48 of the POLE gene, results from a C to G substitution at nucleotide position 6734. The threonine at codon 2245 is replaced by serine, 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.
Fulgent Genetics, Fulgent Genetics RCV002491091 SCV002780456 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 2021-12-28 criteria provided, single submitter clinical testing

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