19-1220595-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000455.5(STK11):c.612C>A(p.Phe204Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F204V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.243

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]

STK11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 96 pathogenic changes around while only 29 benign (77%) in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.612C>A	p.Phe204Leu	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.612C>A	p.Phe204Leu	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1879C>A		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.612C>A	p.Phe204Leu	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.612C>A	p.Phe204Leu	missense_variant	Exon 5 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.240C>A	p.Phe80Leu	missense_variant	Exon 7 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*437C>A		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*437C>A		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1436042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711942

African (AFR)

AF:

0.00

AC:

AN:

32902

American (AMR)

AF:

0.00

AC:

AN:

41364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25524

East Asian (EAS)

AF:

0.00

AC:

AN:

38422

South Asian (SAS)

AF:

0.00

AC:

AN:

83578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099350

Other (OTH)

AF:

0.00

AC:

AN:

59196

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

May 08, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F204L variant (also known as c.612C>A), located in coding exon 5 of the STK11 gene, results from a C to A substitution at nucleotide position 612. The phenylalanine at codon 204 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peutz-Jeghers syndrome

Uncertain:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 204 of the STK11 protein (p.Phe204Leu). This variant is not present in population databases (gnomAD no frequency). 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: 922825). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;D;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.83

.;L;.

PhyloP100

0.24

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.9

.;D;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

.;D;.

Sift4G

Uncertain

0.037

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.62

MutPred

0.45

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;

MVP

0.55

MPC

2.3

ClinPred

0.99

GERP RS

-5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.82

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over