rs587780717

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2

The NM_000455.5(STK11):c.440G>A(p.Arg147His) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 1,561,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R147C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 4.28

Publications

11 publications found

Variant links:

COSMIC-nc: COSV58821114

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 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 44 uncertain in NM_000455.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1219389-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3600330.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2569185).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.440G>A	p.Arg147His	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.440G>A	p.Arg147His	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1707G>A		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.440G>A	p.Arg147His	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.440G>A	p.Arg147His	missense_variant	Exon 3 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.68G>A	p.Arg23His	missense_variant	Exon 5 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*265G>A		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*265G>A		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151078

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:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000229

AC:

AN:

218366

AF XY:

0.0000169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000635

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000623

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000205

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000142

AC:

AN:

1409974

Hom.:

Cov.:

AF XY:

0.0000157

AC XY:

AN XY:

699496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32026

American (AMR)

AF:

0.0000725

AC:

AN:

41396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24504

East Asian (EAS)

AF:

0.0000307

AC:

AN:

32588

South Asian (SAS)

AF:

0.00

AC:

AN:

82616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5492

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1086518

Other (OTH)

AF:

0.0000174

AC:

AN:

57376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41260

American (AMR)

AF:

0.00

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

4868

South Asian (SAS)

AF:

0.000212

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67836

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:2Benign:1

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 arginine with histidine at codon 147 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 35171259), an individual affected with breast cancer (DOI: 10.2298/GENSR1702399A), and an individual affected with colorectal cancer (PMID: 34326862). This variant has been identified in 5/218366 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. -

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Nov 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The STK11 c.440G>A (p.Arg147His) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 34284872 (2022)), colorectal cancer (PMID: 34326862 (2021)), pancreatic cancer (PMID: 35171259 (2022)), various cancer types (PMID: 37937776 (2023)), and reportedly healthy individuals (PMID: 30476936 (2019)). The frequency of this variant in the general population, 0.000023 (5/218366 chromosomes in total 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jul 14, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of sporadic breast cancer (Antov 2017) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jan 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 24, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

not specified

Uncertain:1

Jan 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: STK11 c.440G>A (p.Arg147His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 218366 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.440G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer, colorectal cancer, or pancreatic ductal adenocarcinoma without strong evidence of causality (e.g. Bhai_2021, Krivokuca_2022, Yin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer 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: 35171259, 34326862, 34284872). ClinVar contains an entry for this variant (Variation ID: 135921). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Breast and/or ovarian cancer

Uncertain:1

Jan 06, 2023

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

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

Benign

0.19

BayesDel_addAF

Benign

-0.0081

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.078

Eigen_PC

Benign

0.031

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.6

.;L

PhyloP100

4.3

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.5

.;D

REVEL

Uncertain

0.35

Sift

Benign

0.036

.;D

Sift4G

Uncertain

0.053

T;T

Polyphen

0.17

.;B

Vest4

0.51

MVP

0.81

MPC

1.2

ClinPred

0.50

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.67

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over