NM_000455.5:c.721G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_000455.5(STK11):c.721G>A(p.Ala241Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,178 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A241A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1

Conservation

PhyloP100: 7.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.721G>A	p.Ala241Thr	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.721G>A	p.Ala241Thr	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1988G>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.721G>A	p.Ala241Thr	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.721G>A	p.Ala241Thr	missense_variant	Exon 5 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.349G>A	p.Ala117Thr	missense_variant	Exon 7 of 12	3		ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000829

AC:

AN:

241110

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132230

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:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1457090

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724572

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with a history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754); This variant is associated with the following publications: (PMID: 30287823, 15863673, 25980754) -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 08, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peutz-Jeghers syndrome

Uncertain:4Benign:1

Apr 14, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 241 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/241110 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 08, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A241T variant (also known as c.721G>A), located in coding exon 5 of the STK11 gene, results from a G to A substitution at nucleotide position 721. The alanine at codon 241 is replaced by threonine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.00008 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant has been detected in multiple individuals with no reported features of STK11-associated disease (Ambry internal data). 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. -

Breast and/or ovarian cancer

Uncertain:1

Oct 27, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 1

Uncertain:1

Oct 11, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.031

MutationAssessor

Benign

0.87

.;L

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.50

.;N

REVEL

Uncertain

0.58

Sift

Benign

0.14

.;T

Sift4G

Benign

0.19

T;T

Polyphen

0.87

.;P

Vest4

0.84

MutPred

0.52

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.75

MPC

2.0

ClinPred

0.73

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.87

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over