Submissions for variant NM_000455.5(STK11):c.613G>A (p.Ala205Thr)

gnomAD frequency: 0.00004  dbSNP: rs730881981

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200996	SCV000211713	uncertain significance	not specified	2016-11-08	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.613G>A at the cDNA level, p.Ala205Thr (A205T) at the protein level, and results in the change of an Alanine to a Threonine (GCG>ACG). This variant was observed in at least one woman with triple negative breast cancer (Couch 2015). In a functional study on a head/neck squamous cell carcinoma cell line, this variant impaired the ability of STK11 to suppress cell growth and to decrease kinase activity (Qui 2006). STK11 Ala205Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Ala205Thr occurs at a position that is conserved across species and is located in the protein kinase domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Ala205Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000161003	SCV000213625	likely benign	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000200492	SCV000254554	uncertain significance	Peutz-Jeghers syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 205 of the STK11 protein (p.Ala205Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with triple negative breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 182909). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on STK11 function (PMID: 16407837, 19892943). 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000161003	SCV000679744	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000200492	SCV000784910	uncertain significance	Peutz-Jeghers syndrome	2017-02-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000200492	SCV000839416	uncertain significance	Peutz-Jeghers syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760084	SCV000889864	uncertain significance	not provided	2018-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000161003	SCV000905826	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 205 of the STK11 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study in a head and neck squamous cell carcinoma cell line has shown that this variant results in significant decrease of kinase activity and ability to suppress cell growth compared to wild type protein (PMID: 16407837). This variant has been reported in an individual affected with breast cancer (PMID: 25452441). This variant has been identified in 1/209624 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.
Genome-Nilou Lab	RCV000200492	SCV002057267	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200492	SCV004017968	uncertain significance	Peutz-Jeghers syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003462107	SCV004205585	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-06-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000200492	SCV004816386	uncertain significance	Peutz-Jeghers syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 205 of the STK11 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant results in significant decrease of kinase activity and ability to suppress cell growth (PMID: 16407837). This variant has been reported in an individual affected with breast cancer (PMID: 25452441). This variant has been identified in 1/209624 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.