rs752699287

Positions:

• chr19-1226622-G-A
• chr19-1226622-G-C
• chr19-1226622-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000455.5(STK11):​c.1277G>A​(p.Arg426Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000573 in 1,395,300 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: 0.0000057 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.88

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.252706).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.1277G>A	p.Arg426Gln	missense_variant	9/10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2544G>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1277G>A	p.Arg426Gln	missense_variant	9/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3	c.905G>A	p.Arg302Gln	missense_variant	11/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000684 AC: 1 AN: 146102 Hom.: 0 AF XY: 0.0000125 AC XY: 1 AN XY: 79932

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000573 AC: 8 AN: 1395300 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 688302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000463

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000183 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 426 of the STK11 protein (p.Arg426Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 818777). 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%. 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	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces arginine with glutamine at codon 426 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a breast cancer case-control study conducted in Japan, this variant was detected in 3/7051 female cases, 4/11241 female controls, 0/53 male cases, and 2/12490 male controls (PMID: 30287823). This variant has been identified in 1/146102 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -
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	May 08, 2023	The p.R426Q variant (also known as c.1277G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1277. The arginine at codon 426 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 3 in 7051 unselected breast cancer patients and 4 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	This missense variant replaces arginine with glutamine at codon 426 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a breast cancer case-control study conducted in Japan, this variant was detected in 3/7051 female cases, 4/11241 female controls, 0/53 male cases, and 2/12490 male controls (PMID: 30287823). This variant has been identified in 1/146102 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.58	.;N
REVEL	Benign	0.12
Sift	Uncertain	0.021	.;D
Sift4G	Uncertain	0.034	D;T
Polyphen		0.38	.;B
Vest4		0.46
MutPred		0.26		.;Gain of loop (P = 0.0851);
MVP		0.62
MPC		0.059
ClinPred		0.70	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.14

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: rs752699287; hg19: chr19-1226621;