Submissions for variant NM_000455.5(STK11):c.465-4G>A

dbSNP: rs587780009

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679320	SCV000149508	likely benign	not provided	2021-03-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16287113, 28873162)
Ambry Genetics	RCV000115599	SCV000172815	likely benign	Hereditary cancer-predisposing syndrome	2019-04-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Invitae	RCV000144662	SCV000253256	likely benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213012	SCV000540466	likely benign	not specified	2016-12-15	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a splice variant in intron 3 of STK11 (10 total exons). The variant has been reported in one individual with Peutz Jeghers (Aretz 2005). This variant is has a Max MAF of 0.07% in ExAC (7 South Asian alleles) and 0.04% in gnomAD (12 South Asian alleles). Classified as Likely benign by 3 submitters (GeneDx, Ambry, Invitae) and VUS by Pathway Genomics.
Counsyl	RCV000144662	SCV000785989	uncertain significance	Peutz-Jeghers syndrome	2018-01-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679320	SCV000806082	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115599	SCV000902841	likely benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000144662	SCV001140938	benign	Peutz-Jeghers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262518	SCV001440433	uncertain significance	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798332	SCV002042769	uncertain significance	Breast and/or ovarian cancer	2023-01-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000144662	SCV002057254	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115599	SCV002531702	likely benign	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213012	SCV002761022	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213012	SCV003844611	likely benign	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.465-4G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing. The variant allele was found at a frequency of 8.5e-05 in 223438 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 64 fold of the estimated maximal estimated 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 South Asian origin. c.465-4G>A has been reported in the literature in one individual affected with Peutz-Jeghers Syndrome (Aretz_2005), however authors are unclear about the possible splice impact. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as Benign (n=1), Likely Benign (n=7) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV000144662	SCV004017994	benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115599	SCV005045491	likely benign	Hereditary cancer-predisposing syndrome	2024-03-22	criteria provided, single submitter	clinical testing
Pathway Genomics	RCV000144662	SCV000189991	uncertain significance	Peutz-Jeghers syndrome	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354249	SCV001548813	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 c.465-4G>A variant was identified in 1 of 142 proband chromosomes (frequency: 0.007) from individuals or families with Peutz-Jeghers syndrome (Aretz 2005). The variant was also identified in the following databases: dbSNP (ID: rs587780009) as "With other allele", ClinVar (2x uncertain significance, 3x likely benign), Clinvitae, and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 19 of 220968 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5028 chromosomes (freq: 0.0002), Latino in 4 of 31136 chromosomes (freq: 0.0001), European in 2 of 99398 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 9228 chromosomes (freq: 0.0001), and South Asian in 11 of 27928 chromosomes (freq: 0.0004). The variant was not observed in the African, East Asian, or Finnish populations. The identification of this variant together with a co-occurring pathogenic variant in the PALB2 gene (c.661_662delinsTA, p.Val221X) by our laboratory in one individual with breast cancer increases the likelihood this variant does not have clinical significance. The c.465-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions nor at positions -3 and -5 to -12 which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.