19-1220597-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS2

The NM_000455.5(STK11):c.614C>T(p.Ala205Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,590,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A205T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: 7.80

Publications

3 publications found

Variant links:

COSMIC-nc: COSV107372754

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 -3 ACMG points.

PM1

In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 64 pathogenic changes around while only 21 benign (75%) in NM_000455.5

BP6

Variant 19-1220597-C-T is Benign according to our data. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443. Variant chr19-1220597-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142443.

BS2

High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.614C>T	p.Ala205Val	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.614C>T	p.Ala205Val	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1881C>T		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.614C>T	p.Ala205Val	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.614C>T	p.Ala205Val	missense_variant	Exon 5 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.242C>T	p.Ala81Val	missense_variant	Exon 7 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*439C>T		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*439C>T		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000191

AC:

AN:

209296

AF XY:

0.00000869

show subpopulations

Gnomad AFR exome

AF:

0.0000877

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000271

AC:

AN:

1437938

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

713142

show subpopulations

African (AFR)

AF:

0.0000910

AC:

AN:

32972

American (AMR)

AF:

0.00

AC:

AN:

41472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25540

East Asian (EAS)

AF:

0.00

AC:

AN:

38546

South Asian (SAS)

AF:

0.0000239

AC:

AN:

83786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.0000309

AC:

AN:

1100516

Other (OTH)

AF:

0.00

AC:

AN:

59294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000844

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:6Benign: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. -

Jul 08, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PM2_SUP, PP3 -

Nov 23, 2015

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. -

Jun 04, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 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 valine at codon 205 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 not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 4/209296 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

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Aug 23, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jan 20, 2025

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. -

Nov 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jan 16, 2025

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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19892943, 26154128, 26010451, 15863673) -

not specified

Benign:1

Apr 18, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: STK11 c.614C>T (p.Ala205Val) 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 2.6e-05 in 1590130 control chromosomes (gnomAD v4.0.0). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.614C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 142443). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.56

.;N;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.1

.;D;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.029

.;D;.

Sift4G

Benign

0.15

T;T;T

Polyphen

0.97

.;D;.

Vest4

0.72

MVP

0.68

MPC

1.9

ClinPred

0.66

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.83

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over