Submissions for variant NM_000455.5(STK11):c.1163A>G (p.Lys388Arg)

gnomAD frequency: 0.00001  dbSNP: rs756877141

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589090	SCV000572303	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28900777)
Invitae	RCV000543251	SCV000629069	uncertain significance	Peutz-Jeghers syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 388 of the STK11 protein (p.Lys388Arg). This variant is present in population databases (rs756877141, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 422754). 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 not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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	RCV000569327	SCV000664326	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	clinical testing	The p.K388R variant (also known as c.1163A>G), located in coding exon 9 of the STK11 gene, results from an A to G substitution at nucleotide position 1163. The lysine at codon 388 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589090	SCV000696704	uncertain significance	not provided	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.1163A>G (p.Lys388Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 2/90388 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000394 (2/50760). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS - Possibly Benign.
Mendelics	RCV000543251	SCV000839428	uncertain significance	Peutz-Jeghers syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569327	SCV001351986	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 388 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 STK11-related disorders in the literature. This variant has been identified in 3/240296 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589090	SCV002047278	uncertain significance	not provided	2021-04-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000543251	SCV002057950	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing