Submissions for variant NM_000455.5(STK11):c.1087A>G (p.Thr363Ala)

dbSNP: rs764458789

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479121	SCV000566792	uncertain significance	not provided	2018-11-06	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.1087A>G at the cDNA level, p.Thr363Ala (T363A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Alexander et al. (2010) demonstrated that this variant was not able to be phosphorylated by ATM in response to oxidative stress; however, Ui et al. (2014) subsequently found that phosphorylation may not be required for protein recruitment to double strand break sites. STK11 Thr363Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the c-terminal region (Daniell 2017). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Thr363Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000564324	SCV000672334	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.T363A variant (also known as c.1087A>G), located in coding exon 8 of the STK11 gene, results from an A to G substitution at nucleotide position 1087. The threonine at codon 363 is replaced by alanine, an amino acid with 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.
Invitae	RCV000685209	SCV000812682	uncertain significance	Peutz-Jeghers syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 363 of the STK11 protein (p.Thr363Ala). This variant is present in population databases (rs764458789, gnomAD 0.006%). 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: 419166). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on STK11 function (PMID: 23584481). 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.
Mendelics	RCV000685209	SCV000839426	uncertain significance	Peutz-Jeghers syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564324	SCV001351982	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 363 of the STK11 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. A functional study has shown that Thr363 of the STK11 protein is a phosphorylation site for ATM, ATR and DNA-PKcs kinases and that this variant disrupts such phosphorylation in response to ionizing radiation (PMID: 23584481). However, this study has also shown that Thr363 phosphorylation is not required for STK11 recruitment to the DNA double-strand break sites. The clinical relevance of this observation is not known. This variant has been reported in individuals affected with leukemia (PMID: 32550823). This variant has been identified in 1/244438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Genome-Nilou Lab	RCV000685209	SCV002057921	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing