Submissions for variant NM_000455.5(STK11):c.795G>A (p.Glu265=)

gnomAD frequency: 0.00004  dbSNP: rs730881963

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213019	SCV000211687	benign	not specified	2014-07-11	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.
Ambry Genetics	RCV000160977	SCV000212950	likely benign	Hereditary cancer-predisposing syndrome	2014-07-17	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	RCV000204976	SCV000260114	benign	Peutz-Jeghers syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000204976	SCV000488732	likely benign	Peutz-Jeghers syndrome	2016-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160977	SCV000686690	likely benign	Hereditary cancer-predisposing syndrome	2016-03-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679324	SCV000806086	likely benign	not provided	2017-10-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679324	SCV001134849	benign	not provided	2023-04-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000204976	SCV001140939	likely benign	Peutz-Jeghers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679324	SCV001151579	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	STK11: BP4, BP7
Genome-Nilou Lab	RCV000204976	SCV002057282	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213019	SCV002074229	benign	not specified	2022-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160977	SCV002526938	benign	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204976	SCV004015575	benign	Peutz-Jeghers syndrome	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204976	SCV004017962	benign	Peutz-Jeghers syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492659	SCV004239731	likely benign	Breast and/or ovarian cancer	2022-09-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000204976	SCV004818909	likely benign	Peutz-Jeghers syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358138	SCV001553798	benign	Familial ovarian cancer		no assertion criteria provided	clinical testing	The STK11 p.Glu265= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs730881963) “With Likely benign allele”, ClinVar (classified as benign by GeneDx and likely benign by Ambry Genetics, Invitae and Counsyl), Clinvitae (3x), and in control databases in 50 (1 homozygous) of 275192 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include, other in 4 of 6416 chromosomes (freq. 0.0006), Latino in 18 (1 homozygous) of 34300 chromosomes (freq. 0.0005), European Non-Finnish in 5 of 125550 chromosomes (freq. 0.00004), and South Asian in 23 of 30524 chromosomes (freq. 0.0007); it was not seen in the African, Ashkenazi Jewish, European Finnish, and East Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.6359C>G/ p.Ser2120X), increasing the likelihood that the p.Glu265=variant does not have clinical significance.The p.Glu265= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.