Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001770310 | SCV000544202 | uncertain significance | not provided | 2024-11-22 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 301 of the POLE protein (p.Asp301Asn). This variant is not present in population databases (gnomAD no frequency). 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: 405876). 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. |
| Ambry Genetics | RCV001018660 | SCV001179924 | likely benign | Hereditary cancer-predisposing syndrome | 2024-05-06 | 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. |
| Gene |
RCV001770310 | SCV002003117 | uncertain significance | not provided | 2023-10-03 | 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: 20951805) |
| Baylor Genetics | RCV000472299 | SCV004203549 | uncertain significance | Colorectal cancer, susceptibility to, 12 | 2024-02-02 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004737507 | SCV005348199 | uncertain significance | POLE-related disorder | 2024-06-03 | no assertion criteria provided | clinical testing | The POLE c.901G>A variant is predicted to result in the amino acid substitution p.Asp301Asn. This variant has been reported in a study of patients with colorectal cancer; however, no specific details were provided regarding the pathogenicity of the variant (Table 2, Stenzinger et al. 2014. PubMed ID: 25124163). This variant has also been reported as a somatic change in a colorectal tumor specimen (Guerra et al. 2017. PubMed ID: 29072370). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as uncertain in ClinVar. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |