19-1221295-G-A

Position:

chr19-1221295-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000455.5(STK11):c.817G>A(p.Ala273Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,610,686 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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 4.97

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 -5 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=0.07996693).

BP6

Variant 19-1221295-G-A is Benign according to our data. Variant chr19-1221295-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142052.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
STK11	NM_000455.5 linkuse as main transcript	c.817G>A	p.Ala273Thr	missense_variant	6/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 linkuse as main transcript	c.817G>A	p.Ala273Thr	missense_variant	6/9		NP_001394184.1
STK11	NR_176325.1 linkuse as main transcript	n.2084G>A		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.817G>A	p.Ala273Thr	missense_variant	6/10	1	NM_000455.5	ENSP00000324856	P1	Q15831-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000821

AC:

AN:

243660

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

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:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1458488

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

725342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

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:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 273 of the STK11 protein (p.Ala273Thr). This variant is present in population databases (rs587782199, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26898890, 30287823). ClinVar contains an entry for this variant (Variation ID: 142052). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2017	Variant summary: The STK11 c.817G>A (p.Ala273Thr) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 0.0000101, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. However, this variant was reported in a patient with BrC (Caminsky_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until more definitive clinical and functional studies become available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2023	In the published literature, the variant has been reported in a woman affected with breast cancer (PMID: 26898890 (2016)). This variant was also identified in both affected and unaffected individuals in large-scale breast cancer association studies (PMIDs: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.0000082 (2/243660 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2023	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 breast cancer, but also in unaffected controls (Caminsky et al., 2016; Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 15863673, 30287823, 26898890, 26010451) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2019	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	Jul 29, 2015	- -

Generalized juvenile polyposis/juvenile polyposis coli

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The STK11 p.Ala273Thr variant was identified in 1 of 576 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Caminsky 2016). The variant was also identified in dbSNP (ID: rs587782199) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x in Large intestine). The variant was not identified in MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 2 of 241530 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33228 chromosomes (freq: 0.00003), European in 1 of 109252 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala273 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.060

.;N

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Benign

1.7

.;N

REVEL

Benign

0.16

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.22

MutPred

0.25

Gain of ubiquitination at K269 (P = 0.0797);Gain of ubiquitination at K269 (P = 0.0797);

MVP

0.17

MPC

0.040

ClinPred

0.71

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.063

gMVP

0.16

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