chr19-1221980-C-A

Position:

chr19-1221980-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1PM5BP4_StrongBP6BS1BS2

The NM_000455.5(STK11):c.894C>A(p.Phe298Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,569,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. F298?) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: -0.228

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 -9 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 chr19-1221977-GTT-GC is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.013816625).

BP6

Variant 19-1221980-C-A is Benign according to our data. Variant chr19-1221980-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=6, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000906 (138/152380) while in subpopulation AFR AF= 0.00317 (132/41600). AF 95% confidence interval is 0.00273. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
STK11	NM_000455.5 linkuse as main transcript	c.894C>A	p.Phe298Leu	missense_variant	7/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 linkuse as main transcript	c.894C>A	p.Phe298Leu	missense_variant	7/9		NP_001394184.1
STK11	NR_176325.1 linkuse as main transcript	n.2161C>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.894C>A	p.Phe298Leu	missense_variant	7/10	1	NM_000455.5	ENSP00000324856	P1	Q15831-1

Frequencies

GnomAD3 genomes

AF:

0.000906

AC:

138

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00318

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000172

AC:

AN:

180062

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

96980

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000953

AC:

135

AN:

1416874

Hom.:

Cov.:

AF XY:

0.0000785

AC XY:

AN XY:

700912

show subpopulations

Gnomad4 AFR exome

AF:

0.00353

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152380

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00317

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.00109

ESP6500AA

AF:

0.00154

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2019	- -
Likely benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Phe298Leu variant in STK11 has been reported in 2 individuals with suspected Lynch Syndrome (PMID: 25980754), in the homozygous state in a cervical cancer tumor (PMID: 19340305), and in a primary pancreatic neuroendocrine tumor, cervical cancer tumor, and metastatic pituitary adenoma (PMID: 23893923, 24652667, 27615706). This variant has also been identified in 0.2677% (49/18302) of African chromosomes in individuals without cancer, 0.01403% (4/28506) of Latino chromosomes, and 0.001096% (1/91266) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199681533). This variant has been reported in ClinVar as a VUS and likely benign variant (Variation ID: 127707). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2019	Variant summary: STK11 c.894C>A (p.Phe298Leu) results in a non-conservative amino acid change located in the Serine/Threonine kinase LKB1, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency is approximately 43.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-06), strongly suggesting that the variant is benign. In addition, this variant has been reported in 21/2559 (0.0082) African American women who are cancer free and older than age 70 (Flossies). c.894C>A has been reported in the literature in individuals affected with different type of cancer (Yurgelun_2015, Young_2013, Haiman_2013, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with HBOC. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3475dupA, p.Ile1159fsX6; BRCA1 c.4327C>T, p.Arg1443X), providing supporting evidence for a benign role. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely benign, 4 VUS). Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2017	This variant is denoted STK11 c.894C>A at the cDNA level, p.Phe298Leu (F298L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has been observed in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). STK11 Phe298Leu was observed with an allele frequency of 0.2% (6/3904) in African Americans in the NHLBI Exome Sequencing Project and an allele frequency of 0.3% (4/1322) in the African populations in 1000 Genomes. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. STK11 Phe298Leu occurs at a position where amino acids with properties similar to Phenylalanine are tolerated across species and is located in the protein kinase domain (UniProt). 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 Phe298Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 10, 2022	- -

Peutz-Jeghers syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Apr 30, 2018	The STK11 variant designated as NM_000455.4:c.894C>A (p.Phe298Leu) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 1800 individuals in the population and in 1 out of 200 individuals of African ancestry, which is a higher frequency than expected for a pathogenic STK11 variant (Kobayashi et al, 2017, PMID:28166811). Based on in silico software predictions, this variant is predicted to be tolerated (SIFT, PolyPhen-2). This variant is in ClinVar (Variation ID: 127707) and has been classified as likely benign by three commercial laboratories. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter STK11 function or modify risk for the clinical features of Peutz-Jeghers syndrome. A modest (less than 2 fold) increase in risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 06, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 09, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 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. -

Carcinoma of pancreas

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 13, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

STK11-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.95

.;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.9

.;N

REVEL

Benign

0.29

Sift

Benign

0.43

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

.;B

Vest4

0.36

MutPred

0.41

Gain of disorder (P = 0.1099);Gain of disorder (P = 0.1099);

MVP

0.30

MPC

0.047

ClinPred

0.032

GERP RS

-0.91

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.42

gMVP

0.75

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