19-1223151-A-G

Position:

• chr19-1223151-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000455.5(STK11):​c.1087A>G​(p.Thr363Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 6.68

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphothreonine; by ATM and autocatalysis (size 0) in uniprot entity STK11_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28861642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.1087A>G	p.Thr363Ala	missense_variant	8/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.1087A>G	p.Thr363Ala	missense_variant	8/9		NP_001394184.1
STK11	NR_176325.1	n.2354A>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1087A>G	p.Thr363Ala	missense_variant	8/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.1087A>G	p.Thr363Ala	missense_variant	8/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.715A>G	p.Thr239Ala	missense_variant	10/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244438 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459300 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 725840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 363 of the STK11 protein (p.Thr363Ala). This variant is present in population databases (rs764458789, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 419166). 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 with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on STK11 function (PMID: 23584481). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 29, 2024	The p.T363A variant (also known as c.1087A>G), located in coding exon 8 of the STK11 gene, results from an A to G substitution at nucleotide position 1087. The threonine at codon 363 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Liu Y et al. Front Genet, 2023 Nov;14:1271710). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 24, 2020	This missense variant replaces threonine with alanine at codon 363 of the STK11 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. A functional study has shown that Thr363 of the STK11 protein is a phosphorylation site for ATM, ATR and DNA-PKcs kinases and that this variant disrupts such phosphorylation in response to ionizing radiation (PMID: 23584481). However, this study has also shown that Thr363 phosphorylation is not required for STK11 recruitment to the DNA double-strand break sites. The clinical relevance of this observation is not known. This variant has been reported in individuals affected with leukemia (PMID: 32550823). This variant has been identified in 1/244438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2018

This variant is denoted STK11 c.1087A>G at the cDNA level, p.Thr363Ala (T363A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Alexander et al. (2010) demonstrated that this variant was not able to be phosphorylated by ATM in response to oxidative stress; however, Ui et al. (2014) subsequently found that phosphorylation may not be required for protein recruitment to double strand break sites. STK11 Thr363Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the c-terminal region (Daniell 2017). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Thr363Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.32	T;D;T
Eigen	Benign	0.033
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D;D;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.18	.;T;.
Sift4G	Benign	0.53	T;T;.
Polyphen		0.56	.;P;.
Vest4		0.55
MutPred		0.44		Loss of phosphorylation at T363 (P = 0.017);Loss of phosphorylation at T363 (P = 0.017);.;
MVP		0.51
MPC		0.21
ClinPred		0.42	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs764458789; hg19: chr19-1223150;