Submissions for variant NM_000455.5(STK11):c.735-9G>A

gnomAD frequency: 0.00009  dbSNP: rs201899557

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198727	SCV000253262	benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000583537	SCV000691542	likely benign	Hereditary cancer-predisposing syndrome	2017-09-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284359	SCV001470106	benign	not specified	2020-05-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001284359	SCV001482085	benign	not specified	2021-02-12	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.735-9G>A 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 247564 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 78-fold the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.735-9G>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001354422	SCV001889745	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000198727	SCV002057431	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000583537	SCV002526931	benign	Hereditary cancer-predisposing syndrome	2021-01-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001284359	SCV004242950	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000198727	SCV004822666	likely benign	Peutz-Jeghers syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000583537	SCV005045470	likely benign	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354422	SCV001549035	likely benign	not provided		no assertion criteria provided	clinical testing	The STK11 c.735-9G>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University, and in the Insight Hereditary Tumors databases. The variant was not identified in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs201899557) as with likely benign allele and in the ClinVar and Clinvitae databases as likely benign by Invitae and Color Genomics. The variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002). The variant was identified in control databases in 23 of 245260 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5454 chromosomes (freq: 0.0002), Latino in 17 of 33522 chromosomes (freq: 0.0005), European Non-Finnish in 4 of 111066 chromosomes (freq: 0.00004), East Asian in 1 of 17230 chromosomes (freq: 0.00006), while the variant was not observed in the African, Ashkenazi Jewish, European Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.