NM_000455.5:c.1165G>A

Variant names:

• chr19-1226510-G-A
• rs1555740118
• NM_000455.5:c.1165G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000455.5(STK11):​c.1165G>A​(p.Ala389Thr) 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 benign outcome for this variant. 16/22 in silico tools predict a benign 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. A389S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.826
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15092108).
• BP6: Variant 19-1226510-G-A is Benign according to our data. Variant chr19-1226510-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2782674.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.1165G>A	p.Ala389Thr	missense_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2432G>A		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1165G>A	p.Ala389Thr	missense_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3	c.793G>A	p.Ala265Thr	missense_variant	Exon 11 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*990G>A		non_coding_transcript_exon_variant	Exon 10 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*990G>A		3_prime_UTR_variant	Exon 10 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Aug 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 389 of the STK11 protein (p.Ala389Thr). This variant has not been reported in the literature in individuals affected with STK11-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. -

Hereditary cancer-predisposing syndrome Benign:1

Jun 11, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	.;L
PhyloP100		0.83
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.0	.;N
REVEL	Benign	0.086
Sift	Benign	0.40	.;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0060	.;B
Vest4		0.36
MutPred		0.26		Loss of ubiquitination at K388 (P = 0.0915);Loss of ubiquitination at K388 (P = 0.0915);
MVP		0.42
MPC		0.044
ClinPred		0.17	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.23
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1555740118; hg19: chr19-1226509; COSMIC: COSV53068949;