19-1223080-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The ENST00000326873.12(STK11):​c.1016C>T​(p.Pro339Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,609,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P339A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

STK11
ENST00000326873.12 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 7.60
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.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.902
BS2
High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STK11NM_000455.5 linkuse as main transcriptc.1016C>T p.Pro339Leu missense_variant 8/10 ENST00000326873.12 NP_000446.1
STK11NM_001407255.1 linkuse as main transcriptc.1016C>T p.Pro339Leu missense_variant 8/9 NP_001394184.1
STK11NR_176325.1 linkuse as main transcriptn.2283C>T non_coding_transcript_exon_variant 9/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.1016C>T p.Pro339Leu missense_variant 8/101 NM_000455.5 ENSP00000324856 P1Q15831-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152142
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:
0.00000417
AC:
1
AN:
239814
Hom.:
0
AF XY:
0.00000765
AC XY:
1
AN XY:
130656
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000921
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1456910
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
724266
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:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74316
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
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Aug 27, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 20, 2022The p.P339L variant (also known as c.1016C>T), located in coding exon 8 of the STK11 gene, results from a C to T substitution at nucleotide position 1016. The proline at codon 339 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 11, 2019- -
Peutz-Jeghers syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 07, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 339 of the STK11 protein (p.Pro339Leu). This variant is present in population databases (rs567896256, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 142696). 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 expected to disrupt STK11 protein function with a positive 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. -
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, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 06, 2024Variant summary: STK11 c.1016C>T (p.Pro339Leu) 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 4.2e-06 in 239814 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1016C>T has been reported in the literature in a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), and the variant was reported in 3/60466 cases, but was also found in 1/53461 controls (Dorling_2021, reported through LOVD). In addition, the variant was also reported in gastric and colorectal cancer samples, however it was unclear if it was of somatic-, or germline origin (Miura_2015, Cremolini_2017). 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: 25778705, 33471991, 29045518). ClinVar contains an entry for this variant (Variation ID: 142696). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 06, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25695693, 28900777) -
Melanoma, cutaneous malignant, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJul 23, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;D
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Benign
0.66
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
2.0
.;M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.8
.;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0050
.;D
Sift4G
Uncertain
0.0080
D;D
Polyphen
0.99
.;D
Vest4
0.88
MVP
0.76
MPC
0.29
ClinPred
0.99
D
GERP RS
3.8
Varity_R
0.85
gMVP
0.69

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: rs567896256; hg19: chr19-1223079; API