Submissions for variant NM_000455.5(STK11):c.863-5_863-3del

dbSNP: rs764739106

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483886	SCV000569207	uncertain significance	not provided	2016-01-18	criteria provided, single submitter	clinical testing	This variant is denoted STK11 IVS6-(5_3)delCTC or c.863-(5_3)delCTC and consists of a deletion of three nucleotides at the -3, -4, and -5 positions in intron 6 of the STK11 gene. The normal sequence with the bases that are deleted in braces is tctc[ctc]agGG, where the capital letters are exonic and lowercase are intronic. Multiple in silico models predict this variant to damage the nearby natural acceptor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. STK11 c.863-(5_3)delCTC 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. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The nucleotides that are deleted are not conserved. Based on the currently available information, we consider STK11 c.863-(5_3)delCTC to be a variant of uncertain significance.
Invitae	RCV000704310	SCV000833254	likely benign	Peutz-Jeghers syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018110	SCV001179297	likely benign	Hereditary cancer-predisposing syndrome	2019-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001018110	SCV001346091	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	clinical testing	This variant causes a deletion of 3 nucleotides from the -3 to -5 positions in intron 6 of the STK11 gene. Splice site prediction tools suggest that this variant may have an impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001537796	SCV001750209	likely benign	Hereditary cancer	2021-07-14	criteria provided, single submitter	clinical testing	STK11:c.863-5_863-3del variant was detected in 1 patient without Peutz-Jeghers phenotype. The variants is predicted to abolish natural acceptor splice site in intron 6 by in silico splicing tools. Functional RNA study has shown that the variant causes insignificant splicing aberration (PMID: 34439939). Therefore the variant was classified as likely benign (ACMG/AMP: BS3, BP5, PM2).
Genome-Nilou Lab	RCV000704310	SCV002057290	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824797	SCV002074354	uncertain significance	not specified	2022-01-03	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.863-5_863-3delCTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Four computational tools predict the variant weakens a 3 acceptor site. c.863-5_863-3delCTC has been reported in the literature in an individual that did not have any clinical characteristics of Peutz-Jeghers syndrome. RNAseq analysis of the patient blood sample revealed an abnormal transcript that lacks exon 7. However, this out-of-frame transcript was minorly expressed (only in 0.9%), implying that the variant causes an insignificant splicing abnormality (Dragos_2021). The variant was absent in 159362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Co-occurrence with a pathogenic variant has been observed via internal testing (BRCA2 c.100G>T, p.E34X). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and as likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
MGZ Medical Genetics Center	RCV000704310	SCV002581742	uncertain significance	Peutz-Jeghers syndrome	2022-08-16	criteria provided, single submitter	clinical testing