Submissions for variant NM_000455.5(STK11):c.1254C>G (p.Cys418Trp)

gnomAD frequency: 0.00005  dbSNP: rs587780715

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123057	SCV000166352	benign	Peutz-Jeghers syndrome	2025-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131151	SCV000186093	likely benign	Hereditary cancer-predisposing syndrome	2021-11-04	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	RCV000585976	SCV000211729	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing multigene hereditary cancer panel testing (Shirts 2016); This variant is associated with the following publications: (PMID: 26845104, 27535533, 28900777)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131151	SCV000266231	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000123057	SCV000487848	uncertain significance	Peutz-Jeghers syndrome	2015-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131151	SCV000686608	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/195444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281949	SCV000696708	uncertain significance	not specified	2024-09-03	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1254C>G (p.Cys418Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 164078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1254C>G has not been reported in the literature in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 135918). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000123057	SCV002057996	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123057	SCV004018018	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585976	SCV004221271	uncertain significance	not provided	2022-10-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000073 (6/81688 chromosomes in European (Non-Finnish) 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 an individual undergoing multigene hereditary cancer panel testing (PMID: 26845104 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000585976	SCV004224520	uncertain significance	not provided	2022-05-06	criteria provided, single submitter	clinical testing	BP4, PM2
All of Us Research Program, National Institutes of Health	RCV000123057	SCV004819024	uncertain significance	Peutz-Jeghers syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/195444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000123057	SCV005402336	uncertain significance	Peutz-Jeghers syndrome	2024-04-19	criteria provided, single submitter	clinical testing	The STK11 c.1254C>G (p.Cys418Trp) missense change has a maximum subpopulation frequency of 0.007% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394447	SCV006054139	uncertain significance	Peutz-Jeghers syndrome; Melanoma, cutaneous malignant, susceptibility to, 1; Familial pancreatic carcinoma; Germ cell tumor of testis	2023-06-09	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000123057	SCV000503556	uncertain significance	Peutz-Jeghers syndrome	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 47 year old with a history of colon cancer diagnosed at 47 and a family history of colon cancer.