Submissions for variant NM_000455.5(STK11):c.910C>T (p.Arg304Trp)

dbSNP: rs786201090

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256082	SCV000322048	pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity (Boudeau et al., 2003; Nezu et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15863673, 19369417, 30528796, 32489267, 12552571, 19340305, 10441497, 16407837, 22185227, 12865922, 16707622, 12112668, 17404884, 9809980, 19727776, 15121768, 17761947, 29310834, 30787465)
Invitae	RCV000435642	SCV000541172	pathogenic	Peutz-Jeghers syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the STK11 protein (p.Arg304Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Peutz-Jeghers syndrome (PMID: 9809980, 12865922, 15121768, 17404884). ClinVar contains an entry for this variant (Variation ID: 183802). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function. Experimental studies have shown that this missense change affects STK11 function (PMID: 10441497, 12552571). This variant disrupts the p.Arg304 amino acid residue in STK11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16287113). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000435642	SCV000918283	pathogenic	Peutz-Jeghers syndrome	2017-10-26	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.910C>T (p.Arg304Trp) variant located in the protein kinase domain involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 30938 control chromosomes (gnomAD). Multiple publications have cited the variant in PJS patients. In addition, multiple functional studies, Boudeau_2003 and Nezu_1999, found the variant to cause abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001183047	SCV001348700	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 304 in the kinase domain of the STK11 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of kinase activity (PMID: 10441497, 12552571). This variant has been reported in over 10 individuals affected with Peutz-Jeghers syndrome (PMID: 9809980, 15188174, 16582077, 16707622, 17404884, 19727776, 23415580, 30528796, 37377590) and in an individual affected with bilateral breast cancer and gastric cancer (PMID: 32489267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Genome-Nilou Lab	RCV000435642	SCV002057385	pathogenic	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001183047	SCV002687015	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-11	criteria provided, single submitter	clinical testing	The p.R304W pathogenic mutation (also known as c.910C>T), located in coding exon 7 of the STK11 gene, results from a C to T substitution at nucleotide position 910. The arginine at codon 304 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with Peutz-Jeghers syndrome (Resta N et al. Cancer Res. 1998;58(21):4799; Lim W et al. Br J Cancer. 2003;89:308-313; Schumacher V et al. J Med Genet. 2005;42(5):428-35; Salloch H et al. Int J Colorectal Dis, 2010 Jan;25:97-107; Amos CI et al. J. Med. Genet., 2004 May;41:327-33; Mehenni H et al. Dig. Dis. Sci. 2007 Aug;52(8):1924-33). Functional studies have shown that this alteration leads to inability of STK11 to autophosphorylate, to phosphorylate p53, to suppress the growth of melanoma cells, and it limits protein localization to the nucleus (Boudeau J et al. Hum. Mutat., 2003 Feb;21:172; Nezu J et al. Biochem. Biophys. Res. Commun. 1999 Aug;261(3):750-5). Based on the available evidence, this alteration is classified as a pathogenic mutation.
All of Us Research Program, National Institutes of Health	RCV000435642	SCV004818936	pathogenic	Peutz-Jeghers syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 304 in the kinase domain of the STK11 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of kinase activity (PMID: 10441497, 12552571). This variant has been reported in over 10 individuals affected with Peutz-Jeghers syndrome (PMID: 9809980, 15188174, 16582077, 16707622, 17404884, 19727776, 23415580, 30528796, 37377590) and in an individual affected with bilateral breast cancer and gastric cancer (PMID: 32489267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV000435642	SCV004931342	likely pathogenic	Peutz-Jeghers syndrome	2024-02-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15863673, 19727776, 23415580]. Functional studies indicate this variant impacts protein function [PMID: 10441497, 12552571, 15561763].
Database of Curated Mutations (DoCM)	RCV000435642	SCV000510520	likely pathogenic	Peutz-Jeghers syndrome	2016-05-13	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000256082	SCV001549077	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000256082	SCV001956537	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256082	SCV001966906	pathogenic	not provided		no assertion criteria provided	clinical testing