Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000801661 | SCV000941449 | likely pathogenic | Tumor predisposition syndrome 3 | 2023-10-15 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 7 of the POT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with multiple primary melanoma (PMID: 32325837; Invitae). ClinVar contains an entry for this variant (Variation ID: 647206). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 32325837). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 | RCV002424851 | SCV002742947 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-11 | criteria provided, single submitter | clinical testing | The c.255+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the POT1 gene. This variant was identified in 1/167 Italian individuals with cutaneous melanoma who were CDKN2A/ARF- and CDK4-negative. RNA studies demonstrated that this alteration leads to skipping of coding exon 3 (Pastorino L et al. Cancers (Basel). 2020 04;12:). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |