19-1220434-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000455.5(STK11):c.526G>C(p.Asp176His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D176A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.86

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1220434-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 182907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 19-1220434-G-C is Pathogenic according to our data. Variant chr19-1220434-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3963258.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
STK11	NM_000455.5 link	c.526G>C	p.Asp176His	missense_variant	Exon 4 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 link	c.526G>C	p.Asp176His	missense_variant	Exon 4 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1793G>C		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.526G>C	p.Asp176His	missense_variant	Exon 4 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1 link	c.526G>C	p.Asp176His	missense_variant	Exon 4 of 9			ENSP00000498804.1
STK11	ENST00000585748.3 link	c.154G>C	p.Asp52His	missense_variant	Exon 6 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6 link	n.*351G>C		non_coding_transcript_exon_variant	Exon 5 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6 link	n.*351G>C		3_prime_UTR_variant	Exon 5 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 14, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D176H variant (also known as c.526G>C), located in coding exon 4 of the STK11 gene, results from a G to C substitution at nucleotide position 526. The aspartic acid at codon 176 is replaced by histidine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Peutz-Jeghers syndrome (Salloch H et al. Int J Colorectal Dis, 2010 Jan;25:97-107). Other variant(s) at the same codon, p.D176N (c.526G>A), have been identified in individual(s) with features consistent with Peutz-Jeghers syndrom (de Leng WW et al. Clin. Genet., 2007 Dec;72:568-73; Yang HR et al. Dig. Dis. Sci., 2010 Dec;55:3458-65; Wang Z et al. Hum. Mutat., 2014 Jul;35:851-8; Dai L et al. Dig. Dis. Sci., 2014 Aug;59:1856-61; Chiang JM et al. Asian J Surg, 2018 Sep;41:480-485). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;D;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;H;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.0

.;D;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.99

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Mutation Taster

=9/91

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over