Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000700203 | SCV000828950 | pathogenic | PTEN hamartoma tumor syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 5 of the PTEN 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 PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Cowden syndrome (PMID: 11918710). In at least one individual the variant was observed to be de novo. This variant is also known as c.492delG or IVS5+1delG. ClinVar contains an entry for this variant (Variation ID: 577445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002343521 | SCV002646190 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-10-12 | criteria provided, single submitter | clinical testing | The c.492+1delG intronic pathogenic mutation, located in intron 5 of the PTEN gene, results from a deletion of one nucleotide within intron 5 of the PTEN gene. This alteration has been reported in families with clinical diagnostic features of PTEN hamartoma tumor syndrome and was identified in four affected members from one family (Bussaglia E et al. J Invest Dermatol, 2002 Apr;118:639-44; Merks JH et al. J Med Genet, 2003 Oct;40:e111). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001354193 | SCV001548745 | pathogenic | Malignant tumor of breast | no assertion criteria provided | clinical testing | The PTEN c.492+1delG variant was identified in 1 of 68 proband chromosomes (frequency: 0.02) from an individual or family with Cowden Syndrome (Bussaglia 2002). The variant was also identified in ClinVar (classified as pathogenic by Invitae), LOVD 3.0, and the Zhejiang University database. The variant was not identified in dbSNP or Cosmic database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.492+1delG variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Furthermore, characterization of cryptic splicing study using RT-PCR identify the variant causes exon 5 skipping and results in a frameshift in the PTEN protein at valine 85 and terminates after 13 amino acids (Chen 2017). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |