rs886037859

Variant names:

• chr19-1220450-A-C
• rs886037859
• NM_000455.5:c.542A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-1220450-A-C
• chr19-1220450-A-G
• chr19-1220450-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000455.5(STK11):​c.542A>C​(p.Asn181Thr) 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. N181E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.20
• Publications: 0 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 12 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 27 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 chr19-1220449-AAC-GAA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 576260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-1220450-A-C is Pathogenic according to our data. Variant chr19-1220450-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3963260.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.542A>C	p.Asn181Thr	missense_variant	Exon 4 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.542A>C	p.Asn181Thr	missense_variant	Exon 4 of 9		NP_001394184.1
STK11	NR_176325.1	n.1809A>C		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.542A>C	p.Asn181Thr	missense_variant	Exon 4 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.542A>C	p.Asn181Thr	missense_variant	Exon 4 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.170A>C	p.Asn57Thr	missense_variant	Exon 6 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*367A>C		non_coding_transcript_exon_variant	Exon 5 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*367A>C		3_prime_UTR_variant	Exon 5 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 12, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N181T variant (also known as c.542A>C), located in coding exon 4 of the STK11 gene, results from an A to C substitution at nucleotide position 542. The asparagine at codon 181 is replaced by threonine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Peutz-Jeghers syndrome (Ambry internal data). Another variant at the same codon, p.N181S (c.542A>G) has also been identified in individual(s) with features consistent with Peutz-Jeghers syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, p.N181T is deleterious. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;D;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;H;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.0	.;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.98		Loss of ubiquitination at K178 (P = 0.1099);Loss of ubiquitination at K178 (P = 0.1099);.;
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.99
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs886037859; hg19: chr19-1220449; COSMIC: COSV58820183;