Menu
GeneBe

rs771632414

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_000455.5(STK11):c.976C>A(p.Pro326Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000784 in 764,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. P326L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

15

Clinical Significance

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

Conservation

PhyloP100: 1.45
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 -1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000455.5
BP4
Computational evidence support a benign effect (MetaRNN=0.08187264).
BP6
Variant 19-1223040-C-A is Benign according to our data. Variant chr19-1223040-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184692.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=3}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STK11NM_000455.5 linkuse as main transcriptc.976C>A p.Pro326Thr missense_variant 8/10 ENST00000326873.12
STK11NM_001407255.1 linkuse as main transcriptc.976C>A p.Pro326Thr missense_variant 8/9
STK11NR_176325.1 linkuse as main transcriptn.2243C>A non_coding_transcript_exon_variant 9/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.976C>A p.Pro326Thr missense_variant 8/101 NM_000455.5 P1Q15831-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152074
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
GnomAD4 exome
AF:
0.00000816
AC:
5
AN:
612880
Hom.:
0
Cov.:
31
AF XY:
0.00000900
AC XY:
3
AN XY:
333258
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000146
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152074
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74280
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:
0.0000712
Hom.:
0
ExAC
AF:
0.00000832
AC:
1

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:2Benign:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 12, 2023This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylFeb 01, 2018- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 16, 2023This alteration is classified as likely benign based on a combination of the following: 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 HealthApr 27, 2023This missense variant replaces proline with threonine at codon 326 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 been reported in an individual affected with early-onset breast cancer in the literature (PMID 25503501). This variant has not been identified 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 submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 01, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 18, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with early-onset breast cancer undergoing multi-gene hereditary cancer panel testing (Maxwell et al., 2016); This variant is associated with the following publications: (PMID: 25503501, 28900777) -
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The STK11 p.Pro326Thr variant was identified in 1 of 556 proband chromosomes (frequency: 0.002) from individuals or families with early onset breast cancer (Maxwell 2015). The variant was also identified in dbSNP (ID: rs771632414) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, and two other submitters). The variant was not identified in the LOVD 3.0 database. The variant was identified in control databases in 1 of 219930 chromosomes at a frequency of 0.000005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 98674 chromosomes (freq: 0.00001), but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Pro326 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. -
Melanoma, cutaneous malignant, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsSep 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
Cadd
Benign
11
Dann
Benign
0.83
DEOGEN2
Benign
0.27
T;T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.082
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
0.99
D
PrimateAI
Benign
0.31
T
Sift4G
Benign
0.59
T;T
Polyphen
0.0010
.;B
Vest4
0.18
MutPred
0.30
Gain of phosphorylation at P326 (P = 0.0124);Gain of phosphorylation at P326 (P = 0.0124);
MVP
0.38
MPC
0.045
ClinPred
0.054
T
GERP RS
-1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.029
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs771632414; hg19: chr19-1223039; API