19-1226628-C-G

Position:

chr19-1226628-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP3BP6BS1BS2

The NM_000455.5(STK11):c.1283C>G(p.Ser428Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000101 in 1,390,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S428S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 4.68

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 -6 ACMG points.

PM1

In a mutagenesis_site No effect on kinase activity. (size 0) in uniprot entity STK11_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

BP6

Variant 19-1226628-C-G is Benign according to our data. Variant chr19-1226628-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141156.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=4}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000101 (14/1390190) while in subpopulation AMR AF= 0.0002 (7/35042). AF 95% confidence interval is 0.0000937. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.1283C>G	p.Ser428Trp	missense_variant	9/10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NR_176325.1 link	n.2550C>G		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12 link	c.1283C>G	p.Ser428Trp	missense_variant	9/10	1	NM_000455.5	ENSP00000324856.6		Q15831-1
STK11	ENST00000585748.3 link	c.911C>G	p.Ser304Trp	missense_variant	11/12	3		ENSP00000477641.2		A0A087WT72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000355

AC:

AN:

140794

Hom.:

AF XY:

0.0000259

AC XY:

AN XY:

77184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000213

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1390190

Hom.:

Cov.:

AF XY:

0.00000875

AC XY:

AN XY:

685434

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000200

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:

0.00000372

Gnomad4 OTH exome

AF:

0.0000521

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000186

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 20, 2022	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754); This variant is associated with the following publications: (PMID: 30287823, 11297520, 23612973, 18321849, 28900777, 18854309, 18854318, 36243179, 25980754) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2024	The STK11 c.1283C>G (p.Ser428Trp) variant has been reported in the published literature in an individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 (2015)) and in an individual with breast cancer (PMID: 35534704 (2022)). It has also been found in reportedly healthy individuals (PMIDs: 30287823 (2018) and 36243179 (2022)). The frequency of this variant in the general population, 0.00021 (5/23466 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2020	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2023	Variant summary: STK11 c.1283C>G (p.Ser428Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 140794 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1283C>G has been reported in the literature in an individual being evaluated for Lynch Syndrome (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Laboratories classified the variant as either likely benign (n=4) or VUS (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Peutz-Jeghers syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

2.0

.;M

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.8

.;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0030

.;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

.;D

Vest4

0.65

MutPred

0.35

.;Loss of phosphorylation at S428 (P = 0.0026);

MVP

0.64

MPC

0.32

ClinPred

0.65

GERP RS

3.0

Varity_R

0.45

gMVP

0.46

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