Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001559623 | SCV000653282 | uncertain significance | not provided | 2024-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1436 of the POLE protein (p.Arg1436Trp). This variant is present in population databases (rs764904030, 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: 473659). 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 expected to disrupt POLE protein function with a positive 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. |
| Gene |
RCV001559623 | SCV001781894 | uncertain significance | not provided | 2024-12-10 | criteria provided, single submitter | clinical testing | 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; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29056344, 27149842) |
| Institute of Human Genetics, |
RCV000534433 | SCV002526685 | uncertain significance | Colorectal cancer, susceptibility to, 12 | 2022-05-10 | criteria provided, single submitter | clinical testing | _x000D_ Criteria applied: PP3 |
| Ambry Genetics | RCV004943998 | SCV005481527 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-12-04 | criteria provided, single submitter | clinical testing | The p.R1436W variant (also known as c.4306C>T), located in coding exon 34 of the POLE gene, results from a C to T substitution at nucleotide position 4306. The arginine at codon 1436 is replaced by tryptophan, an amino acid with dissimilar 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 variant remains unclear. |