Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001046625 | SCV001210535 | likely pathogenic | Tumor predisposition syndrome 3 | 2023-12-29 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 14 of the POT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POT1 are known to be pathogenic (PMID: 32155570). This variant is present in population databases (rs750755822, 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: 843910). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Ambry Genetics | RCV002379528 | SCV002702233 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-24 | criteria provided, single submitter | clinical testing | The c.1369+1_1369+5delGTAAG intronic variant results from a deletion of 5 nucleotides within intron 10 of the POT1 gene, and involves the canonical splice donor site. The canonical splice donor site is highly conserved in available vertebrate species. In silico analysis predicts that this alteration will abolish the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This novel donor site, if utilized, would result in an in-frame transcript with unknown functional impact; however, direct evidence is insufficient (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |