19-1226570-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_000455.5(STK11):​c.1225C>T​(p.Arg409Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,588,088 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).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:6

Conservation

PhyloP100: 0.172
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 Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.33304822).
BP6
Variant 19-1226570-C-T is Benign according to our data. Variant chr19-1226570-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135917.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=6}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000854 (13/152252) while in subpopulation AFR AF= 0.000193 (8/41464). AF 95% confidence interval is 0.0000956. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STK11NM_000455.5 linkc.1225C>T p.Arg409Trp missense_variant Exon 9 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NR_176325.1 linkn.2492C>T non_coding_transcript_exon_variant Exon 10 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.1225C>T p.Arg409Trp missense_variant Exon 9 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000585748.3 linkc.853C>T p.Arg285Trp missense_variant Exon 11 of 12 3 ENSP00000477641.2 A0A087WT72

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152252
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000872
AC:
17
AN:
194938
Hom.:
0
AF XY:
0.0000934
AC XY:
10
AN XY:
107116
show subpopulations
Gnomad AFR exome
AF:
0.000296
Gnomad AMR exome
AF:
0.0000339
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000116
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000108
Gnomad OTH exome
AF:
0.000199
GnomAD4 exome
AF:
0.0000383
AC:
55
AN:
1435836
Hom.:
0
Cov.:
31
AF XY:
0.0000379
AC XY:
27
AN XY:
712116
show subpopulations
Gnomad4 AFR exome
AF:
0.000122
Gnomad4 AMR exome
AF:
0.0000242
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000605
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000372
Gnomad4 OTH exome
AF:
0.0000675
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152252
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.000193
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000225
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000123
AC:
1
ExAC
AF:
0.0000595
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:6Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 14, 2023This 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 submitterresearchCSER _CC_NCGL, University of WashingtonOct 01, 2016Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 50 year old female diagnosed with colon cancer at age 49. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 28, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylDec 09, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2025- -
not specified Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalMar 04, 2025- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 18, 2024Variant summary: STK11 c.1225C>T (p.Arg409Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 194938 control chromosomes. The observed variant frequency is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.1225C>T has been reported in the literature as a VUS in individuals with breast cancer (example, Couch_2015, Tung_2014, Goldescu_2018), as an uninformative genotype in a PJS proband who had normal levels of TP53 activity (Jiang_2018), and in unaffected controls in a Japanese population based CRC screening study reporting a final classification as benign (Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 25186627, 17676035, 29785153, 33309985, 30092773). ClinVar contains an entry for this variant (Variation ID: 135917). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo Clinic-- -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 29, 2019- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 29, 2015- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 24, 2022This 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 testingGeneKor MSAAug 01, 2018- -
Likely benign, criteria provided, single submittercurationSema4, Sema4May 04, 2021- -
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 23, 2020In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in one individual with a clinical diagnosis of Peutz-Jeghers syndrome, without a family history of disease, as well as in individuals with breast cancer (Couch 2015, Tung 2015, Goidescu 2018, Jiang 2018); Published functional studies demonstrate no damaging effect: normal P53 activity (Jiang 2018) This variant is associated with the following publications: (PMID: 30287823, 30092773, 31422574, 31159747, 29785153, 25186627, 25925381, 17676035, 25452441) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 20, 2024The STK11 c.1225C>T (p.Arg409Trp) variant has been reported in individuals affected with breast cancer (PMID: 30287823 (2018), 29785153 (2018), 25452441 (2015), 25186627 (2015)). This variant has also been identified in a reportedly healthy individual (PMID: 36243179 (2022)). This variant has been shown to have no deleterious effect on TP53 activity, however, more studies are needed to determine the global effect of this variant on STK11 protein function (PMID: 30092773 (2018)). The frequency of this variant in the general population, 0.0003 (3/10150 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. -
Breast carcinoma Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaMar 09, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.56
D
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.87
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.33
T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
1.8
L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.24
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.99
D
Vest4
0.47
MVP
0.24
MPC
0.23
ClinPred
0.12
T
GERP RS
-2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.16
gMVP
0.33

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: rs368466538; hg19: chr19-1226569; COSMIC: COSV53068501; COSMIC: COSV53068501; API