Submissions for variant NM_000455.5(STK11):c.735-1G>A

dbSNP: rs1057517830

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413399	SCV000490835	pathogenic	not provided	2020-07-09	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16707622, 23240097, 11389158, 17924967, 20559149, 30528796)
Ambry Genetics	RCV000492178	SCV000580908	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-09	criteria provided, single submitter	clinical testing	The c.735-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 6 of the STK11 gene. This pathogenic variant has been reported in multiple individuals with diagnoses consistent with Peutz-Jeghers syndrome (PJS) (Olschwang S et al. J Med Genet. 2001 Jun;38:356-60; Korsse SE et al. J Med Genet. 2013 Jan;50:59-64). Of note, this may be referred to as IVS5-1G>A in some published 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 acceptor site and will 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. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380725	SCV001578877	pathogenic	Peutz-Jeghers syndrome	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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 (PJS) (PMID: 11389158, 23240097). ClinVar contains an entry for this variant (Variation ID: 372522). 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.
Genome-Nilou Lab	RCV001380725	SCV002057378	pathogenic	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001380725	SCV004932352	likely pathogenic	Peutz-Jeghers syndrome	2024-02-12	criteria provided, single submitter	clinical testing	This variant is considered likely 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV001380725	SCV005685054	pathogenic	Peutz-Jeghers syndrome	2025-01-10	criteria provided, single submitter	clinical testing	The following ACMG criteria was used: PVS1; PM2_SUP; PS4_SUP