rs730881982

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_000455.5(STK11):c.632G>A(p.Arg211Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,600,238 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 8.00

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:

STK11 (HGNC:):

STK11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5

BP4

Computational evidence support a benign effect (MetaRNN=0.32563838).

BP6

Variant 19-1220615-G-A is Benign according to our data. Variant chr19-1220615-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=10}.

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5 linkuse as main transcript	c.632G>A	p.Arg211Gln	missense_variant	5/10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 linkuse as main transcript	c.632G>A	p.Arg211Gln	missense_variant	5/9		NP_001394184.1
STK11	NR_176325.1 linkuse as main transcript	n.1899G>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.632G>A	p.Arg211Gln	missense_variant	5/10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 linkuse as main transcript	c.632G>A	p.Arg211Gln	missense_variant	5/9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 linkuse as main transcript	c.260G>A	p.Arg87Gln	missense_variant	7/12	3		ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000448

AC:

AN:

223198

Hom.:

AF XY:

0.0000407

AC XY:

AN XY:

122726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000310

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.0000509

Gnomad NFE exome

AF:

0.0000507

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1448060

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

719164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0000472

Gnomad4 FIN exome

AF:

0.0000984

Gnomad4 NFE exome

AF:

0.0000145

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000503

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:6Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 13, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with glutamine at codon 211 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. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 25186627, 33471991). This variant has been identified in 10/223198 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. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2021	Variant summary: STK11 c.632G>A (p.Arg211Gln) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 223198 control chromosomes (gnomAD v2.1 exomes dataset). The observed variant frequency is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. The variant, c.632G>A, has been reported in the literature in 3 individuals affected breast cancer (Tung_2015, Dorling_2021). These reports however, do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2023	This missense variant replaces arginine with glutamine at codon 211 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. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 25186627, 33471991). This variant has been identified in 10/223198 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. -

Peutz-Jeghers syndrome;C0153594:Malignant tumor of testis;C0235974:Carcinoma of pancreas

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 13, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 27, 2021

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 15863673, 25186627) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;T

Eigen

Benign

0.050

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.92

.;L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.58

.;N;.

REVEL

Benign

0.21

Sift

Benign

0.30

.;T;.

Sift4G

Benign

0.51

T;T;T

Polyphen

0.045

.;B;.

Vest4

0.86

MVP

0.94

MPC

1.1

ClinPred

0.14

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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