Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000560025 | SCV000655167 | uncertain significance | Tumor predisposition syndrome 3 | 2024-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 614 of the POT1 protein (p.Asn614Ser). This variant is present in population databases (rs202024401, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 475066). 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 POT1 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 | RCV000565348 | SCV000674420 | likely benign | Hereditary cancer-predisposing syndrome | 2018-04-12 | 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 |
RCV001755898 | SCV001995390 | uncertain significance | not provided | 2023-07-10 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate single stranded-DNA binding similar to wildtype, suggesting no impact on POT1-telomere complex formation (Simonin-Wilmer et al., 2022); This variant is associated with the following publications: (PMID: 28393830, 36539277) |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001755898 | SCV005626174 | uncertain significance | not provided | 2024-11-11 | criteria provided, single submitter | clinical testing | The POT1 c.1841A>G (p.Asn614Ser) variant has been reported in the published literature in a reportedly healthy individual (PMID: 36539277 (2022)). The frequency of this variant in the general population, 0.000031 (4/127872 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Fulgent Genetics, |
RCV005034117 | SCV005666445 | uncertain significance | Tumor predisposition syndrome 3; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8; Cerebroretinal microangiopathy with calcifications and cysts 3 | 2024-01-17 | criteria provided, single submitter | clinical testing |