rs376280361

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

The ENST00000326873.12(STK11):c.911G>A(p.Arg304Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,570,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

STK11
ENST00000326873.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 7.57

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in ENST00000326873.12

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1221997-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
STK11	NM_000455.5 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	7/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	7/9		NP_001394184.1
STK11	NR_176325.1 linkuse as main transcript	n.2178G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	7/10	1	NM_000455.5	ENSP00000324856	P1	Q15831-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000387

AC:

AN:

180804

Hom.:

AF XY:

0.0000410

AC XY:

AN XY:

97514

show subpopulations

Gnomad AFR exome

AF:

0.000103

Gnomad AMR exome

AF:

0.0000361

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000412

Gnomad FIN exome

AF:

0.000184

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000176

AC:

AN:

1418518

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

701900

show subpopulations

Gnomad4 AFR exome

AF:

0.0000619

Gnomad4 AMR exome

AF:

0.0000258

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000271

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.0000408

Gnomad4 NFE exome

AF:

0.0000156

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000258

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 27, 2023	This missense variant replaces arginine with glutamine at codon 304 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 7/180804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg304Trp and p.Arg304Pro, are known to be pathogenic (Clinvar variation ID: 183802, 428783), indicating that arginine at this position is important for STK11 function. Due to the lack of clinical data, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 304 of the STK11 protein (p.Arg304Gln). 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 variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 419419). 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 80%. 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: 9809980, 10441497, 12552571, 12865922, 15121768, 17404884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9809980, 17404884, 15121768, 12865922, 12552571, 10441497, 35264596, 15863673, 33471991) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2024	The p.R304Q variant (also known as c.911G>A), located in coding exon 7 of the STK11 gene, results from a G to A substitution at nucleotide position 911. The arginine at codon 304 is replaced by glutamine, an amino acid with highly similar properties. In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Two other missense alterations at the same codon, p.R304W and p.R204P, have been reported in individuals with Peutz-Jeghers syndrome (Resta N et al. Cancer Res. 1998;58(21):4799; Lim W et al. Br J Cancer. 2003;89:308-313; Schumacher V et al. J Med Genet. 2005;42(5):428-35; Aretz S et al. Hum Mutat. 2005 Dec;26(6):513-9; Salloch H et al. Int J Colorectal Dis. 2010;25(1):97-107; Amos CI et al. J Med Genet. 2006;41(5):327-333); however, p.R304Q has been identified in numerous individuals without features of PJS (Ambry Internal Data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant 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	Sep 27, 2023	This missense variant replaces arginine with glutamine at codon 304 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 7/180804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg304Trp and p.Arg304Pro, are known to be pathogenic (Clinvar variation ID: 183802, 428783), indicating that arginine at this position is important for STK11 function. Due to the lack of clinical data, 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

STK11-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

The STK11 c.911G>A variant is predicted to result in the amino acid substitution p.Arg304Gln. This variant was reported in an individual with breast cancer and interpreted as uncertain (Table S3 Guindalini et al 2022. PubMed ID: 35264596). Two different missense change at the same amino acid position, c.910C>T (Arg304Trp) and c.911G>C (Arg304Pro), have been reported in patients with colon cancer and Peutz-Jeghers Syndrome (Resta et al. 1998. PubMed ID: 9809980; Boudeau et al. 2003. PubMed ID: 12552571; Mehenni et al. 2007. PubMed ID: 17404884, Aretz et al. 2005. PubMed ID: 16287113, Jiang et al. 2018. PubMed ID: 30092773). The c.911G>A variant is reported in 0.018% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1221996-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.52

.;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

.;N

REVEL

Uncertain

0.57

Sift

Benign

0.18

.;T

Sift4G

Benign

0.15

T;T

Polyphen

0.96

.;D

Vest4

0.73

MVP

0.78

MPC

0.13

ClinPred

0.15

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over