ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1225C>T (p.Arg409Trp) (rs368466538)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123056 SCV000166351 uncertain significance Peutz-Jeghers syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 409 of the STK11 protein (p.Arg409Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs368466538, ExAC 0.04%). This variant has been observed in individuals affected with breast cancer (PMID: 25452441, 25186627, 29785153) and in an individual affected with Peutz-Jeghers syndrome (PMID: 30092773). ClinVar contains an entry for this variant (Variation ID: 135917). This variant has been reported not to substantially affect STK11 protein function (PMID: 30092773). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131250 SCV000186212 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000656985 SCV000279190 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1225C>T at the cDNA level, p.Arg409Trp (R409W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been reported in one individual with a clinical diagnosis of Peutz-Jeghers syndrome, without a family history of disease (Jiang 2018), as well as in individuals with breast cancer (Couch 2015, Tung 2015, Goidescu 2018). Functional studies of this variant demonstrated normal P53 activity (Jiang 2018). STK11 Arg409Trp was observed at an allele frequency of 0.03% (3/9,878) in individuals of African ancestry in large population cohorts (Lek 2016). STK11 Arg409Trp is located in the C-terminal region (Hearle 2006). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Arg409Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000123056 SCV000487954 uncertain significance Peutz-Jeghers syndrome 2015-12-09 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000123056 SCV000700141 uncertain significance Peutz-Jeghers syndrome 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 50 year old female diagnosed with colon cancer at age 49. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
GeneKor MSA RCV000131250 SCV000822204 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000123056 SCV000839431 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656985 SCV000888639 uncertain significance not provided 2019-02-06 criteria provided, single submitter clinical testing
Color RCV000131250 SCV000902743 likely benign Hereditary cancer-predisposing syndrome 2015-09-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000216380 SCV000920272 uncertain significance not specified 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The c.1225C>T (p.Arg409Trp) in STK11 gene is a missense change that involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant is located at the very end of the protein, outside of any known functional domain or repeat region . The variant was observed in the large and broad cohorts of gnomAD project at an allele frequency of 0.00008 (16/189992 chrs tested). The latter frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.000006). The variant was identified in at least one patient presented with TN-BrC without strong evidence in causality and has not, to our knowledge, been reported in individuals with Peutz-Jeghers syndrome. Although several reputable databases/diagnostic centers classified the variant as "VUS", they are likely to have not utilized evidence derived from the most recent version of the control databases (namely gnomAD). Furthermore, at least two entries in ClinVar are not supported by a classification rationale. Even though, based on the frequency data, the variant may represent a benign functional polymorphism, the possibility of a reduced penetrance cannot be ruled out. Due to the lack of the functional studies and limited evidence data, the variant was classified as VUS-Possibly Benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414992 SCV000492581 uncertain significance Breast carcinoma 2016-03-09 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000216380 SCV000692056 uncertain significance not specified no assertion criteria provided clinical testing

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