rs730881981
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_000455.5(STK11):c.613G>A(p.Ala205Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,589,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
STK11
NM_000455.5 missense
NM_000455.5 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 9.86
Genes affected
STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
BP4
Computational evidence support a benign effect (MetaRNN=0.3797617).
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.613G>A | p.Ala205Thr | missense_variant | 5/10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NM_001407255.1 | c.613G>A | p.Ala205Thr | missense_variant | 5/9 | NP_001394184.1 | ||
STK11 | NR_176325.1 | n.1880G>A | non_coding_transcript_exon_variant | 6/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.613G>A | p.Ala205Thr | missense_variant | 5/10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000652231.1 | c.613G>A | p.Ala205Thr | missense_variant | 5/9 | ENSP00000498804.1 | ||||
STK11 | ENST00000585748.3 | c.241G>A | p.Ala81Thr | missense_variant | 7/12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000477 AC: 1AN: 209624Hom.: 0 AF XY: 0.00000868 AC XY: 1AN XY: 115212
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GnomAD4 exome AF: 0.0000132 AC: 19AN: 1437702Hom.: 0 Cov.: 32 AF XY: 0.0000112 AC XY: 8AN XY: 712894
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74316
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 13, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2023 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2016 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 18, 2024 | The STK11 c.613G>A (p.Ala205Thr) variant has been reported in the published literature in in individuals with breast cancer (PMID: 25452441 (2015), 33471991 (2021), 35264596 (2022), see also LOVD (http://databases.lovd.nl/shared/genes/STK11)) and gastric cancer (PMID: 34326862 (2021)). Experimental evidence regarding the effect of this variant on protein function is conflicting (PMID: 16407837 (2006), 19892943 (2009)). The frequency of this variant in the general population, 0.0000048 (1/209624 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Melanoma, cutaneous malignant, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 20, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.
REVEL
Benign
Sift
Benign
.;T;.
Sift4G
Benign
T;T;T
Polyphen
0.69
.;P;.
Vest4
MVP
MPC
1.4
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at