Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001201578 | SCV001372654 | pathogenic | PTEN hamartoma tumor syndrome | 2022-11-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in partial retention of intron 1 and skipping of exon 2 and introduces a premature termination codon (PMID: 11886535). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 933378). This variant is also known as IVS2+1G>A. Disruption of this splice site has been observed in individuals with clinical features of PTEN-related conditions (PMID: 11886535, 23335809). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002402569 | SCV002707688 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-18 | criteria provided, single submitter | clinical testing | The c.164+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the PTEN gene. This alteration was reported in a 73-year-old female with a breast cancer diagnosis at 50 and clinical history of multinodular goiter, moderate macrocephaly, gastrointestinal polyps, facial trichilemmomas, polypoid mucosal lesions of the mouth, nasal papules, and acral keratoses (Trojan J et al. J Invest Dermatol, 2001 Dec;117:1650-3). In addition to the clinical data presented in the literature, another alteration impacting the same donor site (c.164+1G>T) has been detected in an individual diagnosed with Cowden syndrome or Cowden syndrome-like disease (Ngeow J et al. J Clin Oncol, 2014 Jun;32:1818-24). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Trojan J et al. J Invest Dermatol, 2001 Dec;117:1650-3; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
| Myriad Genetics, |
RCV003449641 | SCV004188839 | pathogenic | Cowden syndrome 1 | 2023-09-26 | 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: 17526800, 11886535]. |