rs587782199

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000455.5(STK11):​c.817G>A​(p.Ala273Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,610,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A273V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 4.97
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1
In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 89 pathogenic changes around while only 17 benign (84%) in NM_000455.5
BP4
Computational evidence support a benign effect (MetaRNN=0.07996693).
BP6
Variant 19-1221295-G-A is Benign according to our data. Variant chr19-1221295-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142052.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.
BS2
High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STK11NM_000455.5 linkuse as main transcriptc.817G>A p.Ala273Thr missense_variant 6/10 ENST00000326873.12
STK11NM_001407255.1 linkuse as main transcriptc.817G>A p.Ala273Thr missense_variant 6/9
STK11NR_176325.1 linkuse as main transcriptn.2084G>A non_coding_transcript_exon_variant 7/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.817G>A p.Ala273Thr missense_variant 6/101 NM_000455.5 P1Q15831-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000821
AC:
2
AN:
243660
Hom.:
0
AF XY:
0.0000151
AC XY:
2
AN XY:
132690
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000910
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1458488
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
725342
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 09, 2023- -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthNov 30, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 07, 2023This 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. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 08, 2023In 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. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 14, 2017Variant 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 14, 2023Not 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) -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 11, 2019This 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. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 29, 2015- -
Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.21
T;T
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.85
T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.080
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.060
.;N
MutationTaster
Benign
0.99
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
1.7
.;N
REVEL
Benign
0.16
Sift
Benign
1.0
.;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
.;B
Vest4
0.22
MutPred
0.25
Gain of ubiquitination at K269 (P = 0.0797);Gain of ubiquitination at K269 (P = 0.0797);
MVP
0.17
MPC
0.040
ClinPred
0.71
D
GERP RS
2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.063
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587782199; hg19: chr19-1221294; COSMIC: COSV58821658; COSMIC: COSV58821658; API