rs398123405

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The ENST00000326873.12(STK11):​c.877G>A​(p.Glu293Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E293Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

STK11
ENST00000326873.12 missense

Scores

1
10
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.27
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 -2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 uncertain in ENST00000326873.12
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STK11NM_000455.5 linkuse as main transcriptc.877G>A p.Glu293Lys missense_variant 7/10 ENST00000326873.12 NP_000446.1
STK11NM_001407255.1 linkuse as main transcriptc.877G>A p.Glu293Lys missense_variant 7/9 NP_001394184.1
STK11NR_176325.1 linkuse as main transcriptn.2144G>A non_coding_transcript_exon_variant 8/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.877G>A p.Glu293Lys missense_variant 7/101 NM_000455.5 ENSP00000324856 P1Q15831-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000116
AC:
2
AN:
172130
Hom.:
0
AF XY:
0.0000217
AC XY:
2
AN XY:
92326
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000848
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000425
AC:
6
AN:
1410818
Hom.:
0
Cov.:
30
AF XY:
0.00000717
AC XY:
5
AN XY:
697290
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000250
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000368
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.00000868
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJun 28, 2023This missense variant replaces glutamic acid with lysine at codon 293 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/172130 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 13, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 293 of the STK11 protein (p.Glu293Lys). 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 breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 142641). 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 80%. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 12, 2023This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 23, 2022This missense variant replaces glutamic acid with lysine at codon 293 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/172130 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Uncertain
0.063
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;T
Eigen
Benign
-0.075
Eigen_PC
Benign
0.0090
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.52
D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.0
.;L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-2.4
.;N
REVEL
Uncertain
0.46
Sift
Uncertain
0.0040
.;D
Sift4G
Uncertain
0.012
D;D
Polyphen
0.22
.;B
Vest4
0.52
MutPred
0.60
Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);
MVP
0.63
MPC
0.046
ClinPred
0.67
D
GERP RS
3.6
Varity_R
0.49
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs398123405; hg19: chr19-1221962; API