Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001380249 | SCV001578244 | pathogenic | Peutz-Jeghers syndrome | 2023-12-26 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 5 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Peutz-Jeghers syndrome (PMID: 11389158, 24652667). This variant is also known as IVS5+1g>a. ClinVar contains an entry for this variant (Variation ID: 1068630). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001380249 | SCV001748833 | pathogenic | Peutz-Jeghers syndrome | 2021-06-26 | criteria provided, single submitter | clinical testing | Variant summary: STK11 c.734+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 239620 control chromosomes (gnomAD). c.734+1G>A has been reported in the literature in individuals affected with Peutz-Jeghers Syndrome (e.g. Olschwang_2001, Lim_2003, Wang_2014, Zhang_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Genome- |
RCV001380249 | SCV002057377 | pathogenic | Peutz-Jeghers syndrome | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002384545 | SCV002674953 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-03 | criteria provided, single submitter | clinical testing | The c.734+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the STK11 gene. This variant has been detected in multiple individuals and/or families diagnosed with Peutz-Jeghers Syndrome (Olschwang S et al. J Med Genet, 2001 Jun;38:356-60; Lim W et al. Br J Cancer, 2003 Jul;89:308-13; Wang Z et al. Hum Mutat, 2014 Jul;35:851-8; Ambry internal data). Of note, this variant is also designated as IVS5+1G>A in some literature. 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 donor site and may result in the creation or strengthening of a novel 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 a disease-causing mutation. |