Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000632836 | SCV000754032 | pathogenic | Peutz-Jeghers syndrome | 2021-04-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with clinical features of Peutz Jeghers syndrome (PMID: 30528796, Invitae). ClinVar contains an entry for this variant (Variation ID: 527837). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the STK11 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 STK11 are known to be pathogenic (PMID: 15188174, 16287113). |
| Ambry Genetics | RCV003362870 | SCV004062265 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-24 | criteria provided, single submitter | clinical testing | The c.598-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 of the STK11 gene. This alteration was identified amongst a cohort of 54 Chinese patients with a clinical diagnosis of Peutz-Jeghers syndrome (Jiang YL et al. Cancer Genet, 2019 Jan;230:47-57). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with STK11-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 may result in the creation or strengthening of a novel splice acceptor 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |