rs553752236

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000455.5(STK11):c.1045G>A(p.Glu349Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,611,590 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. E349A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 3.92

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09029716).

BP6

Variant 19-1223109-G-A is Benign according to our data. Variant chr19-1223109-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127697.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5}.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
STK11	NM_000455.5 linkuse as main transcript	c.1045G>A	p.Glu349Lys	missense_variant	8/10	ENST00000326873.12
STK11	NM_001407255.1 linkuse as main transcript	c.1045G>A	p.Glu349Lys	missense_variant	8/9
STK11	NR_176325.1 linkuse as main transcript	n.2312G>A		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.1045G>A	p.Glu349Lys	missense_variant	8/10	1	NM_000455.5	P1	Q15831-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000491

AC:

AN:

244542

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133334

show subpopulations

Gnomad AFR exome

AF:

0.0000669

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

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:

0.0000144

AC:

AN:

1459294

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

725782

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

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

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 18, 2020	The STK11 c.1045G>A; p.Glu349Lys variant (rs553752236) has been reported in an individual with breast cancer but also in a healthy control (Momozawa 2018). This variant is reported in the ClinVar database (Variation ID: 127697). It is found in the general population with an overall allele frequency of 0.005% (13/275920 alleles, including 1 homozygote) in the Genome Aggregation Database. The glutamate at codon 349 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2017	This variant is denoted STK11 c.1045G>A at the cDNA level, p.Glu349Lys (E349K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as a germline variant. However, it has been reported as a somatic variant in an individual with medullary thyroid cancer and in an individual with cervical cancer (Ji 2015, Lou 2015). STK11 Glu349Lys was observed at an allele frequency of 0.041% (3/7388) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Glu349Lys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Glu349Lys is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2021	- -

Peutz-Jeghers syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

B Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Aug 08, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 03, 2017

Variant summary: The STK11 c.1045G>A (p.Glu349Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 13/273218 control chromosomes in gnomAD at a frequency of 0.0000476, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. This variant was reported in one case of medullary thyroid cancer as a somatic variant (Ji_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.32

T;D

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.93

.;N

REVEL

Benign

0.15

Sift

Benign

0.46

.;T

Sift4G

Benign

0.63

T;T

Polyphen

0.023

.;B

Vest4

0.25

MVP

0.64

MPC

0.047

ClinPred

0.032

GERP RS

2.8

Varity_R

0.099

gMVP

0.36

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