Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001564480 | SCV000544126 | uncertain significance | not provided | 2025-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 781 of the POLE protein (p.Ala781Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 405802). 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 |
RCV001564480 | SCV001787655 | uncertain significance | not provided | 2019-12-19 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016) |
| Mendelics | RCV002248672 | SCV002519179 | uncertain significance | not specified | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004943861 | SCV005478882 | likely benign | Hereditary cancer-predisposing syndrome | 2024-12-09 | 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. |