ClinVar Miner

Submissions for variant NM_000455.5(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 2020-10-29 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), an individual affected with Peutz-Jeghers syndrome (PMID: 30092773) and individuals undergoing multigene panel testing for hereditary cancer (PMID: 31159747). 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 2020-05-19 criteria provided, single submitter clinical testing ​The p.R409W variant (also known as c.1225C>T), located in coding exon 9 of the STK11 gene, results from a C to T substitution at nucleotide position 1225. The arginine at codon 409 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11), and in 1/2158 individuals with breast cancer referred for BRCA1/2 testing (Tung N et al. Cancer. 2015 Jan;121:25-33). A male patient with Peutz-Jeghers syndrome has been reported to have this variant (Jiang YL et al. BMC Med. Genet. 2018 08;19:141). This alteration has been reported with a carrier frequency of 0.0003 in 7051 unselected breast cancer patients and 0.00009 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 Health, Inc RCV000131250 SCV000902743 likely benign Hereditary cancer-predisposing syndrome 2015-09-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000216380 SCV000920272 likely benign not specified 2021-03-08 criteria provided, single submitter clinical testing Variant summary: STK11 c.1225C>T (p.Arg409Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 194938 control chromosomes. The observed variant frequency is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.1225C>T has been reported in the literature as a VUS in individuals with breast cancer (example, Couch_2015, Tung_2014, Goldescu_2018), as an uninformative genotype in a PJS proband who had normal levels of TP53 activity (Jiang_2018), and in unaffected controls in a Japanese population based CRC screening study reporting a final classification as benign (Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=9; likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely 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 Laboratories, Mayo Clinic RCV000216380 SCV000692056 uncertain significance not specified no assertion criteria provided clinical testing

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