Submissions for variant NM_000455.5(STK11):c.598-7G>A

gnomAD frequency: 0.00008  dbSNP: rs377502057

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198089	SCV000253259	likely benign	Peutz-Jeghers syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000198089	SCV000489043	likely benign	Peutz-Jeghers syndrome	2016-08-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001579937	SCV000602232	benign	not provided	2023-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580069	SCV000686668	likely benign	Hereditary cancer-predisposing syndrome	2015-10-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001579937	SCV001943048	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798668	SCV002042772	likely benign	Breast and/or ovarian cancer	2022-09-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000198089	SCV002057264	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000507461	SCV002552017	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580069	SCV002659702	likely benign	Hereditary cancer-predisposing syndrome	2014-12-11	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.
Myriad Genetics, Inc.	RCV000198089	SCV004017910	likely benign	Peutz-Jeghers syndrome	2023-04-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
PreventionGenetics, part of Exact Sciences	RCV003895264	SCV004716688	likely benign	STK11-related disorder	2023-10-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000198089	SCV004822665	likely benign	Peutz-Jeghers syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507461	SCV005185238	benign	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.598-7G>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. Consensus agreement among computation 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 6.1e-05 in 196798 control chromosomes. The observed variant frequency is approximately 10 fold of 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 benign. To our knowledge, no occurrence of c.598-7G>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 215740). Based on the evidence outlined above, the variant was classified as benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357691	SCV001553235	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The STK11 c.598-7G>A variant was not identified in the literature nor was it identified in MutDB, Zhejiang University Database or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs377502057) “With Likely benign allele”, ClinVar (classified as likely benign by Invitae, Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano, and Color Genomics Inc.), Cosmic (1x in a carcinoma of the prostate), and LOVD 3.0 (1x). The variant was also identified in control databases in 17 of 223852 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017); the variant was observed in the following populations: European Non-Finnish in 14 of 97910 chromosomes (freq: 0.0001), Latino in 1 of 29348 chromosomes (freq: 0.00003), and South Asian in 2 of 26370 chromosomes (freq: 0.00008), while not observed in the African, Other, Ashkenazi Jewish, East Asian or Finnish populations. The c.598-7G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Although positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579937	SCV001809112	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001579937	SCV001906430	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001579937	SCV001922785	likely benign	not provided		no assertion criteria provided	clinical testing