Submissions for variant NM_000455.5(STK11):c.597+1G>T

dbSNP: rs886039554

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254989	SCV000322375	pathogenic	not provided	2016-10-28	criteria provided, single submitter	clinical testing	The c.597+1 G>T splice site variant in the STK11 gene has been previously reported in association with Peutz-Jeghers syndrome (Mehenni et al., 2006). This variant destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is pathogenic.
Ambry Genetics	RCV000492737	SCV000580933	likely pathogenic	Hereditary cancer-predisposing syndrome	2013-12-20	criteria provided, single submitter	clinical testing	​The c.597+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 4 of the STK11 gene. This alteration has been described in a patient with Peutz-Jeghers syndrome with colon cancer (Mehenni H et al. Gut 2006; 55:984-90). Two other alterations at this nucleotide (c.597+1G>A and c.597+1G>C) have also been described in patients with Peutz-Jeghers syndrome (Papp J et al. BMC Med. Genet. 2010; 11:169, Hearle N et al. Clin. Cancer Res. 2006; 12:3209-15). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 20,000 alleles tested) in our clinical cohort (includes this individual). This nucleotide position is completely conserved on sequence alignment.Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish or significantly weaken the native splice donor site, respectively. However, direct evidence is unavailable.Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.597+1G>T variant is classified as likely pathogenic.
Invitae	RCV000700997	SCV000829777	pathogenic	Peutz-Jeghers syndrome	2018-03-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This variant has been reported in at least one individual affected with Peutz-Jeghers syndrome (PMID: 16407375). The variant is also known as IVS4+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 265451). A different variant affecting this nucleotide (c.597+1G>A) has been determined to be pathogenic (PMID: 21118512). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 4 of the STK11 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Genome-Nilou Lab	RCV000700997	SCV002057368	pathogenic	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing