rs763353991

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000455.5(STK11):c.463G>A(p.Gly155Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G155E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense, splice_region

Scores

Splicing: ADA: 0.001546

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 9.70

Publications

4 publications found

Variant links:

COSMIC-nc: COSV105889104

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 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.463G>A	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.463G>A	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1730G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.463G>A	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.463G>A	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.91G>A	p.Gly31Arg	missense_variant, splice_region_variant	Exon 5 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*288G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*288G>A		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

196374

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1429942

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

708332

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32940

American (AMR)

AF:

0.00

AC:

AN:

40426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25514

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37868

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097024

Other (OTH)

AF:

0.00

AC:

AN:

59178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000846

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:4

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with arginine at codon 155 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 hereditary cancer in the literature. This variant has not been identified 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. -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.G155R in STK11 (NM_000455.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. is novel (not in any individuals) in gnomAD ExomesThe p.G155R variant is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glycine and arginine. The p.G155R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 155 of STK11 is conserved in all mammalian species. The nucleotide c.463 in STK11 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 155 of the STK11 protein (p.Gly155Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 234791). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

May 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with arginine at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant did not impact autophosphorylation activity (PMID: 34849607). This variant has been reported in individuals affected with breast cancer (PMID: 34326862). This variant has not been identified 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. -

Mar 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G155R variant (also known as c.463G>A), located in coding exon 3 of the STK11 gene, results from a G to A substitution at nucleotide position 463. The glycine at codon 155 is replaced by arginine, an amino acid with dissimilar properties. This alteration demonstrated retained autophosphorylation activity in an in vitro kinase assay (Donnelly LL et al. Carcinogenesis, 2021 Dec;42:1428-1438). 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 is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Jan 29, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: STK11 c.463G>A (p.Gly155Arg) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, the variant is located close to a splice-site, therefore could also affect splicing: consensus agreement among computation tools predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.1e-06 in 1424252 control chromosomes (gnomAD v4). c.463G>A has been reported in the literature in individuals affected with a personal and/or family history of (unspecified) cancer (Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated no damaging effect for this variant (Donnelly_2021). ClinVar contains an entry for this variant (Variation ID: 234791). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Oct 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and family history of breast cancer (Bhai et al., 2021); Published functional studies demonstrate no damaging effect (Donnelly et al., 2021); This variant is associated with the following publications: (PMID: 15863673, 34326862, 34849607) -

Melanoma, cutaneous malignant, susceptibility to, 1

Uncertain:1

Aug 18, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.019

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.17

.;N

PhyloP100

9.7

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.1

.;N

REVEL

Uncertain

0.38

Sift

Benign

0.45

.;T

Sift4G

Benign

0.58

T;T

Polyphen

0.80

.;P

Vest4

0.94

MutPred

0.53

Loss of catalytic residue at C158 (P = 0.0867);Loss of catalytic residue at C158 (P = 0.0867);

MVP

0.65

MPC

1.2

ClinPred

0.91

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.93

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.062

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over