Submissions for variant NM_000455.5(STK11):c.116G>T (p.Arg39Leu)

gnomAD frequency: 0.00001  dbSNP: rs786203250

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166477	SCV000217275	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-31	criteria provided, single submitter	clinical testing	The p.R39L variant (also known as c.116G>T), located in coding exon 1 of the STK11 gene, results from a G to T substitution at nucleotide position 116. The arginine at codon 39 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in a proband with a diagnosis of Cowden syndrome and a germline pathogenic mutation in PTEN (Lopez C et al. Cancer Genomics Proteomics;15(2):115-120). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000204326	SCV000261322	uncertain significance	Peutz-Jeghers syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 39 of the STK11 protein (p.Arg39Leu). This variant is present in population databases (rs786203250, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 29496690). ClinVar contains an entry for this variant (Variation ID: 186826). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. 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.
GeneDx	RCV000222577	SCV000279174	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9809980, 29496690)
Color Diagnostics, LLC DBA Color Health	RCV000166477	SCV000686600	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 39 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 29496690) and in an individual with a diagnosis of Cowden syndrome and a frameshift mutation in exon 1 of PTEN (c.17_18delAA; PMID: 29496690). This variant has been identified in 2/248072 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	RCV000780767	SCV000918293	uncertain significance	not specified	2018-07-02	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.116G>T (p.Arg39Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245434 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.116G>T, has been reported in the literature in individuals affected with Breast Cancer (Tung_2014) and as a somatic event in Colorectal Cancer patients (Betge_2015). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000204326	SCV002057743	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000204326	SCV004816316	uncertain significance	Peutz-Jeghers syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 39 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 29496690) and in an individual with a diagnosis of Cowden syndrome and a frameshift mutation in exon 1 of PTEN (c.17_18delAA; PMID: 29496690). This variant has been identified in 2/248072 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.