Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001027078 | SCV001189580 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-09 | criteria provided, single submitter | clinical testing | The c.802-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 8 of the PTEN gene. This alteration has been reported in the literature in a 45-year-old man with a history of an overall polyp burden of more than 100 polyps, macrocephaly and classic mucocutaneous findings including trichilemmomas and oral papillomas consistent with a diagnosis of Cowden Syndrome (Modi RM et al. Clin Gastroenterol Hepatol, 2017 08;15:e131-e132). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor 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 a disease-causing mutation. |
| Invitae | RCV001385103 | SCV001584848 | pathogenic | PTEN hamartoma tumor syndrome | 2020-05-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individuals affected with Cowden syndrome (PMID: 27477328, 28677221). ClinVar contains an entry for this variant (Variation ID: 827401). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Myriad Genetics, |
RCV003316824 | SCV004018641 | pathogenic | Cowden syndrome 1 | 2023-05-10 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28677221, 28013114]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221]. |