19-1221996-C-T

Variant names:

• chr19-1221996-C-T
• rs786201090
• NM_000455.5:c.910C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000455.5(STK11):​c.910C>T​(p.Arg304Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R304Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 0.219
• Publications: 24 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 34 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 chr19-1221997-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-1221996-C-T is Pathogenic according to our data. Variant chr19-1221996-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.910C>T	p.Arg304Trp	missense	Exon 7 of 10	NP_000446.1
	STK11	NM_001407255.1		c.910C>T	p.Arg304Trp	missense	Exon 7 of 9	NP_001394184.1
	STK11	NR_176325.1		n.2177C>T		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.910C>T	p.Arg304Trp	missense	Exon 7 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.910C>T	p.Arg304Trp	missense	Exon 7 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.538C>T	p.Arg180Trp	missense	Exon 9 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418606 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701954

African (AFR) AF: 0.00 AC: 0 AN: 32314

American (AMR) AF: 0.00 AC: 0 AN: 38786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 36926

South Asian (SAS) AF: 0.00 AC: 0 AN: 80720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090964

Other (OTH) AF: 0.00 AC: 0 AN: 58732

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000233 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:6

Feb 12, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15863673, 19727776, 23415580]. Functional studies indicate this variant impacts protein function [PMID: 10441497, 12552571, 15561763].

Oct 26, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The STK11 c.910C>T (p.Arg304Trp) variant located in the protein kinase domain involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 30938 control chromosomes (gnomAD). Multiple publications have cited the variant in PJS patients. In addition, multiple functional studies, Boudeau_2003 and Nezu_1999, found the variant to cause abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Aug 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 304 in the kinase domain of the STK11 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of kinase activity (PMID: 10441497, 12552571). This variant has been reported in over 10 individuals affected with Peutz-Jeghers syndrome (PMID: 9809980, 15188174, 16582077, 16707622, 17404884, 19727776, 23415580, 30528796, 37377590) and in an individual affected with bilateral breast cancer and gastric cancer (PMID: 32489267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the STK11 protein (p.Arg304Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Peutz-Jeghers syndrome (PMID: 9809980, 12865922, 15121768, 17404884). ClinVar contains an entry for this variant (Variation ID: 183802). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. Experimental studies have shown that this missense change affects STK11 function (PMID: 10441497, 12552571). This variant disrupts the p.Arg304 amino acid residue in STK11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16287113). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

not provided Pathogenic:3 Uncertain:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity (Boudeau et al., 2003; Nezu et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15863673, 19369417, 30528796, 32489267, 12552571, 19340305, 10441497, 16407837, 22185227, 12865922, 16707622, 12112668, 17404884, 9809980, 19727776, 15121768, 17761947, 29310834, 30787465)

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 304 in the kinase domain of the STK11 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of kinase activity (PMID: 10441497, 12552571). This variant has been reported in over 10 individuals affected with Peutz-Jeghers syndrome (PMID: 9809980, 15188174, 16582077, 16707622, 17404884, 19727776, 23415580, 30528796, 37377590) and in an individual affected with bilateral breast cancer and gastric cancer (PMID: 32489267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Aug 29, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.910C>T (p.R304W) alteration is located in exon 7 (coding exon 7) of the STK11 gene. This alteration results from a C to T substitution at nucleotide position 910, causing the arginine (R) at amino acid position 304 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with Peutz-Jeghers syndrome (Resta, 1998; Lim, 2003; Amos, 2004; Schumacher, 2005; Mehenni, 2007; Salloch, 2010). This amino acid position is highly conserved in available vertebrate species. Functional studies have shown that this alteration leads to inability of STK11 to autophosphorylate, to phosphorylate p53, to suppress the growth of melanoma cells, and it limits protein localization to the nucleus (Nezu, 1999; Boudeau, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.22
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.85		Loss of disorder (P = 0.0064)
MVP		0.95
MPC		0.30
ClinPred		0.95	D
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.88
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs786201090; hg19: chr19-1221995; COSMIC: COSV58820334; COSMIC: COSV58820334;