Submissions for variant NM_000455.5(STK11):c.1225C>T (p.Arg409Trp)

dbSNP: rs368466538

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123056	SCV000166351	likely benign	Peutz-Jeghers syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131250	SCV000186212	likely benign	Hereditary cancer-predisposing syndrome	2022-05-24	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.
GeneDx	RCV000656985	SCV000279190	likely benign	not provided	2020-07-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in one individual with a clinical diagnosis of Peutz-Jeghers syndrome, without a family history of disease, as well as in individuals with breast cancer (Couch 2015, Tung 2015, Goidescu 2018, Jiang 2018); Published functional studies demonstrate no damaging effect: normal P53 activity (Jiang 2018) This variant is associated with the following publications: (PMID: 30287823, 30092773, 31422574, 31159747, 29785153, 25186627, 25925381, 17676035, 25452441)
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	2023-01-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0003 (3/10150 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals affected with breast cancer (PMIDs: 30287823 (2018), 29785153 (2018), 25452441 (2015), and 25186627 (2015)). This variant has been shown to have a wild type effect on p53 activity in vitro, however, more studies are needed to determine the global effect of this variant on STK11 protein function (PMID: 30092773 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	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	2024-04-18	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. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 25186627, 17676035, 29785153, 33309985, 30092773). ClinVar contains an entry for this variant (Variation ID: 135917). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000123056	SCV002057334	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000216380	SCV002065862	uncertain significance	not specified	2019-03-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131250	SCV002531662	likely benign	Hereditary cancer-predisposing syndrome	2021-05-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000216380	SCV002761034	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123056	SCV004017987	uncertain significance	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Revvity Omics, Revvity	RCV000123056	SCV004237907	uncertain significance	Peutz-Jeghers syndrome	2023-06-28	criteria provided, single submitter	clinical testing
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