Submissions for variant NM_000455.5(STK11):c.894C>A (p.Phe298Leu)

gnomAD frequency: 0.00100  dbSNP: rs199681533

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213024	SCV000149512	uncertain significance	not specified	2017-09-14	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.894C>A at the cDNA level, p.Phe298Leu (F298L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has been observed in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). STK11 Phe298Leu was observed with an allele frequency of 0.2% (6/3904) in African Americans in the NHLBI Exome Sequencing Project and an allele frequency of 0.3% (4/1322) in the African populations in 1000 Genomes. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. STK11 Phe298Leu occurs at a position where amino acids with properties similar to Phenylalanine are tolerated across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Phe298Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115603	SCV000172929	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000195949	SCV000254560	benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213024	SCV000602240	benign	not specified	2022-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213024	SCV000696730	benign	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.894C>A (p.Phe298Leu) results in a non-conservative amino acid change located in the Serine/Threonine kinase LKB1, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency is approximately 43.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-06), strongly suggesting that the variant is benign. In addition, this variant has been reported in 21/2559 (0.0082) African American women who are cancer free and older than age 70 (Flossies). c.894C>A has been reported in the literature in individuals affected with different type of cancer (Yurgelun_2015, Young_2013, Haiman_2013, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with HBOC. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3475dupA, p.Ile1159fsX6; BRCA1 c.4327C>T, p.Arg1443X), providing supporting evidence for a benign role. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely benign, 4 VUS). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003891609	SCV000806089	likely benign	STK11-related condition	2020-12-14	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).
Mendelics	RCV000195949	SCV000839419	benign	Peutz-Jeghers syndrome	2023-08-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000195949	SCV000886443	likely benign	Peutz-Jeghers syndrome	2018-04-30	criteria provided, single submitter	research	The STK11 variant designated as NM_000455.4:c.894C>A (p.Phe298Leu) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 1800 individuals in the population and in 1 out of 200 individuals of African ancestry, which is a higher frequency than expected for a pathogenic STK11 variant (Kobayashi et al, 2017, PMID:28166811). Based on in silico software predictions, this variant is predicted to be tolerated (SIFT, PolyPhen-2). This variant is in ClinVar (Variation ID: 127707) and has been classified as likely benign by three commercial laboratories. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter STK11 function or modify risk for the clinical features of Peutz-Jeghers syndrome. A modest (less than 2 fold) increase in risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Diagnostics, LLC DBA Color Health	RCV000115603	SCV000902745	likely benign	Hereditary cancer-predisposing syndrome	2015-10-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000195949	SCV001285137	benign	Peutz-Jeghers syndrome	2019-05-06	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000213024	SCV001423028	likely benign	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Phe298Leu variant in STK11 has been reported in 2 individuals with suspected Lynch Syndrome (PMID: 25980754), in the homozygous state in a cervical cancer tumor (PMID: 19340305), and in a primary pancreatic neuroendocrine tumor, cervical cancer tumor, and metastatic pituitary adenoma (PMID: 23893923, 24652667, 27615706). This variant has also been identified in 0.2677% (49/18302) of African chromosomes in individuals without cancer, 0.01403% (4/28506) of Latino chromosomes, and 0.001096% (1/91266) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199681533). This variant has been reported in ClinVar as a VUS and likely benign variant (Variation ID: 127707). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).
Baylor Genetics	RCV001293890	SCV001482560	uncertain significance	Carcinoma of pancreas	2019-01-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000195949	SCV002057297	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000213024	SCV002069598	uncertain significance	not specified	2019-08-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115603	SCV002526956	likely benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114259	SCV003800397	likely benign	not provided	2022-04-18	criteria provided, single submitter	clinical testing