Submissions for variant NM_000455.5(STK11):c.1185A>G (p.Thr395=)

gnomAD frequency: 0.00047  dbSNP: rs370207155

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123054	SCV000166349	benign	Peutz-Jeghers syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000213032	SCV000171895	benign	not specified	2014-03-24	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	RCV000128303	SCV000212865	likely benign	Hereditary cancer-predisposing syndrome	2014-06-18	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.
PreventionGenetics, part of Exact Sciences	RCV000213032	SCV000304386	likely benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000123054	SCV000488889	likely benign	Peutz-Jeghers syndrome	2016-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128303	SCV000686602	likely benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586467	SCV000696705	benign	not provided	2017-02-09	criteria provided, single submitter	clinical testing	Variant summary: The c.1185A>G (p.Thr395=) in STK11 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0004106 (31/75494 chrs tested), predominantly in individuals of European origin (0.0006144; 26/42320 chrs). The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant in this gene (0.0000156), suggesting that it is a benign polymorphism. The variant was identified in at least 1 HBOC pt without strong evidence for causality. The variant of interest has been cited as Benign by multiple reputable databases/clinical laboratories. Taking together, the variant was classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213032	SCV000888637	benign	not specified	2019-08-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000123054	SCV001140948	likely benign	Peutz-Jeghers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586467	SCV001151581	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	STK11: BP4, BP7
Illumina Laboratory Services, Illumina	RCV000123054	SCV001287491	uncertain significance	Peutz-Jeghers syndrome	2018-10-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798402	SCV002042762	likely benign	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000123054	SCV002057327	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000213032	SCV002065851	benign	not specified	2021-03-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128303	SCV002531652	benign	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213032	SCV002552038	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123054	SCV004017988	benign	Peutz-Jeghers syndrome	2023-04-14	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.
True Health Diagnostics	RCV000128303	SCV000788214	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357027	SCV001552351	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 p.Thr395= variant was identified in 1 of 66 proband chromosomes (frequency: 0.02) from Australian individuals or families with Peutz–Jeghers Syndrome (Chow 2006). The variant was also identified in dbSNP (ID: rs370207155) “With other allele”, ClinVar (classified benign by Invitae, GeneDx and likely benign by Ambry Genetics, Prevention Genetics and Counsyl), Clinvitae (3x), Zhejiang Colon Cancer Database (1x), but was not identified in Cosmic, LOVD 3.0, and Insight Hereditary Tumors Database. The variant was identified in control databases in 125 of 263502 chromosomes at a frequency of 0.0005 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 4 of 22240 chromosomes (frequency: 0.0002), Other in 2 of 6164 chromosomes (frequency: 0.0003), Latino in 8 of 33706 chromosomes (frequency: 0.0002), European Non-Finnish in 79 of 119338 chromosomes (frequency: 0.0006),and European Finnish in 32 of 24350 chromosomes (frequency: 0.001). The p.Thr395= 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. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586467	SCV001809166	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000586467	SCV001921664	likely benign	not provided		no assertion criteria provided	clinical testing