Submissions for variant NM_000455.5(STK11):c.817G>A (p.Ala273Thr)

gnomAD frequency: 0.00001  dbSNP: rs587782199

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130859	SCV000185758	likely benign	Hereditary cancer-predisposing syndrome	2019-04-11	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	RCV000196939	SCV000254558	uncertain significance	Peutz-Jeghers syndrome	2023-12-07	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 273 of the STK11 protein (p.Ala273Thr). This variant is present in population databases (rs587782199, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26898890, 30287823). ClinVar contains an entry for this variant (Variation ID: 142052). 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.
GeneDx	RCV000587949	SCV000569217	uncertain significance	not provided	2023-06-14	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; Observed in individuals with breast cancer, but also in unaffected controls (Caminsky et al., 2016; Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 15863673, 30287823, 26898890, 26010451)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587949	SCV000696726	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.817G>A (p.Ala273Thr) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 0.0000101, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. However, this variant was reported in a patient with BrC (Caminsky_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until more definitive clinical and functional studies become available.
Color Diagnostics, LLC DBA Color Health	RCV000130859	SCV000905485	likely benign	Hereditary cancer-predisposing syndrome	2015-07-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587949	SCV001134851	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in a woman affected with breast cancer (PMID: 26898890 (2016)). This variant was also identified in both affected and unaffected individuals in large-scale breast cancer association studies (PMIDs: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.0000082 (2/243660 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Genome-Nilou Lab	RCV000196939	SCV002057283	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000196939	SCV004237906	uncertain significance	Peutz-Jeghers syndrome	2023-06-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000196939	SCV004818912	likely benign	Peutz-Jeghers syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356427	SCV001551591	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli		no assertion criteria provided	clinical testing	The STK11 p.Ala273Thr variant was identified in 1 of 576 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Caminsky 2016). The variant was also identified in dbSNP (ID: rs587782199) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x in Large intestine). The variant was not identified in MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 2 of 241530 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33228 chromosomes (freq: 0.00003), European in 1 of 109252 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala273 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.