ClinVar Miner

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

gnomAD frequency: 0.00073  dbSNP: rs199681533
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Total submissions: 15
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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 In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000195949 SCV000254560 likely benign Peutz-Jeghers syndrome 2021-12-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213024 SCV000602240 uncertain significance not specified 2017-01-04 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,PreventionGenetics RCV000213024 SCV000806089 likely benign not specified 2020-12-14 criteria provided, single submitter clinical testing
Mendelics RCV000195949 SCV000839419 uncertain significance Peutz-Jeghers syndrome 2018-07-02 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 Institute Rare Disease Group, Broad Institute 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,; 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

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