Submissions for variant NM_000455.5(STK11):c.921-10G>A

gnomAD frequency: 0.00006  dbSNP: rs183406870

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128300	SCV000171892	benign	not specified	2014-05-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000200730	SCV000253266	benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000200730	SCV000488016	likely benign	Peutz-Jeghers syndrome	2015-12-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000128300	SCV000602242	benign	not specified	2020-03-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579573	SCV000686704	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128300	SCV000920283	benign	not specified	2018-10-19	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.921-10G>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. 5/5 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 0.00018 in 178932 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 166.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Hereditary Breast and Ovarian Cancer phenotype (1.6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.921-10G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.3261delC), providing supporting evidence for a benign role. Four 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.
Genome-Nilou Lab	RCV000200730	SCV002057448	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579573	SCV002526960	benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149876	SCV003838189	likely benign	Breast and/or ovarian cancer	2021-06-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200730	SCV004018010	likely benign	Peutz-Jeghers syndrome	2023-04-14	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	RCV003925271	SCV004740727	likely benign	STK11-related disorder	2019-05-16	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	RCV000200730	SCV004822667	likely benign	Peutz-Jeghers syndrome	2023-11-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357217	SCV001552611	likely benign	not provided		no assertion criteria provided	clinical testing	The STK11 c.921-10G>A variant was identified as a somatic change in 1 of 114 proband chromosomes (frequency: 0.009) from an individual with adenocarcinoma of the cervix (Kuragaki 2003). The variant was also identified in the following databases: dbSNP (ID: rs183406870) as "With Likely benign allele", ClinVar (3x likely benign, 2x benign), Clinvitae, and Cosmic (1x, confirmed somatic, in tumour of the cervix). The variant was not identified in MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 32 of 178932 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 32 of 12228 chromosomes (freq: 0.003), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The c.921-10G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, 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, 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.