Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000486681 | SCV000544000 | uncertain significance | not provided | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1457 of the POLE protein (p.Gly1457Val). This variant is present in population databases (rs776534749, gnomAD 0.07%). 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: 405685). 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. |
| Gene |
RCV000486681 | SCV000569428 | uncertain significance | not provided | 2023-08-18 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with hereditary breast/ovarian or colorectal cancer (Velazquez et al., 2020); This variant is associated with the following publications: (PMID: 32522261) |
| Ambry Genetics | RCV000563246 | SCV000671372 | likely benign | Hereditary cancer-predisposing syndrome | 2024-02-27 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781763 | SCV000920067 | likely benign | not specified | 2017-09-12 | criteria provided, single submitter | clinical testing | Variant summary: The POLE c.4370G>T (p.Gly1457Val) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 31/246270 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000685 (23/33582). This frequency is about 48 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. Multiple clinical diagnostic laboratories classified this variant as uncertain significance, prior to incorporation of gnomAD data. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as likely benign. |