Submissions for variant NM_000455.5(STK11):c.5A>C (p.Glu2Ala)

gnomAD frequency: 0.00001  dbSNP: rs1159551738

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581495	SCV000691529	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 2 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 1/193850 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811637	SCV000951913	uncertain significance	Peutz-Jeghers syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2 of the STK11 protein (p.Glu2Ala). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 492547). Invitae Evidence 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 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	RCV001764711	SCV001998927	uncertain significance	not provided	2019-09-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000811637	SCV002057703	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581495	SCV002657550	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-07	criteria provided, single submitter	clinical testing	The p.E2A variant (also known as c.5A>C), located in coding exon 1 of the STK11 gene, results from an A to C substitution at nucleotide position 5. The glutamic acid at codon 2 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003459450	SCV004205540	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2024-03-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001764711	SCV004221284	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (1/38566 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in a healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/STK11)). 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.