rs587782032

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1PM5BP4_ModerateBP6BS2

The NM_000455.5(STK11):c.559G>A(p.Gly187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,606,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. G187?) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:7

Conservation

PhyloP100: 0.532

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 Likely_benign. Variant got -3 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1220466-CGG-CT is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.10190928).

BP6

Variant 19-1220467-G-A is Benign according to our data. Variant chr19-1220467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141815.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=5}.

BS2

High AC in GnomAdExome4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
STK11	NM_000455.5 linkuse as main transcript	c.559G>A	p.Gly187Ser	missense_variant	4/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 linkuse as main transcript	c.559G>A	p.Gly187Ser	missense_variant	4/9		NP_001394184.1
STK11	NR_176325.1 linkuse as main transcript	n.1826G>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.559G>A	p.Gly187Ser	missense_variant	4/10	1	NM_000455.5	ENSP00000324856	P1	Q15831-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

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:

0.0000339

AC:

AN:

236080

Hom.:

AF XY:

0.0000389

AC XY:

AN XY:

128484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000578

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000469

Gnomad OTH exome

AF:

0.000347

GnomAD4 exome

AF:

0.0000392

AC:

AN:

1454774

Hom.:

Cov.:

AF XY:

0.0000470

AC XY:

AN XY:

723048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000442

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

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

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000333

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2022	DNA sequence analysis of the STK11 gene demonstrated a sequence change, c.559G>A, in exon 4 that results in an amino acid change, p.Gly187Ser. This sequence has been previously described in individuals with breast cancer, small cell lung cancers (NSCLC) and has also been described in control population (PMIDs: 25452441, 30287823, 20082862 and FLOSSIES database). This sequence change has been described in the gnomAD database in eight individuals which corresponds to a population frequency of 0.003% (dbSNP rs587782032). The p.Gly187Ser change affects a poorly conserved amino acid residue located in a domain of the STK11 protein that is known to be functional. The p.Gly187Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly187Ser change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2019	Variant summary: STK11 c.559G>A (p.Gly187Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR039154) 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 4.6e-05 in 284338 control chromosomes (gnomAD and publication data). 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 (PJS) phenotype (6.3e-06), strongly suggesting that the variant is benign. Though the variant, c.559G>A, has been reported in the literature in individuals affected with lung-, and breast cancer (Kim_2010, Couch_2015, Momozawa_ 2018), in one of these cases it was noted that the affected patient did not have any clinical manifestations of PJS (Kim_2010); moreover the variant was also reported in multiple healthy controls (Kim_2010, Momozawa_ 2018 and in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 30, 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	curation	Sema4, Sema4	Oct 20, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2017	This variant is denoted STK11 c.559G>A at the cDNA level, p.Gly187Ser (G187S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant was observed in at least one individual with triple negative breast cancer (Couch 2015). STK11 Gly187Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly187Ser occurs at a position that is not conserved and is located in the protein kinase domain and in the region required for binding of substrate and initiation of phospho transfer (UniProt, Hearle 2006). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Gly187Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The STK11 p.Gly187Ser variant was identified in 3 of 10699 proband chromosomes (frequency: 0.0003) from triple negative BRCA families and Japanese women with breast cancer and was present in 2 of 11241 control chromosomes (frequency: 0.00018) from healthy individuals (Couch 2015, Momozawa 20118). The variant was also identified in dbSNP (ID: rs587782032) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (5x as uncertain significance and 1x as likely benign by Ambry Genetics, Invitae, GeneDx, Integrated Genetics, Counsyl, Mendelics) and LOVD 3.0 (4x as uncertain significance). The variant was identified in control databases in 7 of 233812 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5256 chromosomes (freq: 0.0002), European Non-Finnish in 5 of 105720 chromosomes (freq: 0.00005) and East Asian in 1 of 16594 chromosomes (freq: 0.00006), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish or South Asian populations. The p.Gly187 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.36

DANN

Benign

0.82

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.85

T;D;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.82

.;L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

0.54

.;N;.

REVEL

Benign

0.18

Sift

Benign

0.063

.;T;.

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.23

MVP

0.52

MPC

0.97

ClinPred

0.032

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.48

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