Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003225069 | SCV000543937 | uncertain significance | not provided | 2025-02-02 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 73 of the POLE protein (p.Asp73Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 405626). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. |
| Laboratory for Molecular Medicine, |
RCV000826024 | SCV000967513 | uncertain significance | not specified | 2018-08-14 | criteria provided, single submitter | clinical testing | The p.Asp73Gly variant in POLE has not been previously reported in individuals w ith colorectal cancer but has been reported by other clinical laboratories in Cl inVar (Variation ID: 405626). It has also been identified in 1/111706 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org). Computational prediction tools and conservation analysis suggest that the p.Asp73Gly variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of the p.Asp73Gly variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2. |
| Fulgent Genetics, |
RCV002502616 | SCV002814902 | 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 | 2022-04-07 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003225069 | SCV003921553 | uncertain significance | not provided | 2023-04-24 | 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 pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344) |
| Mayo Clinic Laboratories, |
RCV003225069 | SCV005408435 | uncertain significance | not provided | 2023-11-22 | criteria provided, single submitter | clinical testing |