19-1219388-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 5P and 9B. PM1PM5PP3BP6BS1BS2

The NM_000455.5(STK11):c.439C>T(p.Arg147Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000145 in 1,584,166 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.51

Publications

2 publications found

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 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 -4 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.785

BP6

Variant 19-1219388-C-T is Benign according to our data. Variant chr19-1219388-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216431.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000133 (19/1432494) while in subpopulation SAS AF = 0.0000843 (7/83038). AF 95% confidence interval is 0.0000389. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1706C>T		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.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.67C>T	p.Arg23Cys	missense_variant	Exon 5 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*264C>T		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*264C>T		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000226

AC:

AN:

221264

AF XY:

0.00000835

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000246

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000133

AC:

AN:

1432494

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

711024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32736

American (AMR)

AF:

0.0000237

AC:

AN:

42228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25462

East Asian (EAS)

AF:

0.0000795

AC:

AN:

37748

South Asian (SAS)

AF:

0.0000843

AC:

AN:

83038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00000729

AC:

AN:

1097596

Other (OTH)

AF:

0.00

AC:

AN:

58922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.0000264

AC:

AN:

151672

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74070

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41350

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.000210

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.0000357

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000333

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:4Benign:1

Apr 12, 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 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 cysteine at codon 147 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/252572 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. -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Feb 17, 2023

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. -

Sep 11, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Mar 04, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 147 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 6/252572 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. -

not provided

Uncertain:1

Sep 05, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with melanoma (PMID: 34326862); This variant is associated with the following publications: (PMID: 26979979, 15863673, 32459922, 34326862) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

4.5

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.7

.;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.074

T;T

Polyphen

1.0

.;D

Vest4

0.73

MutPred

0.54

Loss of disorder (P = 0.0451);Loss of disorder (P = 0.0451);

MVP

0.85

MPC

2.2

ClinPred

0.94

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.77

Mutation Taster

=64/36

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