19-1220450-A-G

Position:

• chr19-1220450-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.542A>G​(p.Asn181Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.20

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 19-1220450-A-G is Pathogenic according to our data. Variant chr19-1220450-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.542A>G	p.Asn181Ser	missense_variant	4/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.542A>G	p.Asn181Ser	missense_variant	4/9		NP_001394184.1
STK11	NR_176325.1	n.1809A>G		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.542A>G	p.Asn181Ser	missense_variant	4/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.542A>G	p.Asn181Ser	missense_variant	4/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.170A>G	p.Asn57Ser	missense_variant	6/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 27, 2018	This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to be de novo in an individual with features consistent with Peutz-Jeghers syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 254654). This sequence change replaces asparagine with serine at codon 181 of the STK11 protein (p.Asn181Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital	Aug 24, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 06, 2020	This missense variant replaces asparagine with serine at codon 181 in the active site of the kinase domain of the STK11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported by an external laboratory to be de novo in an individual with features consistent with Peutz-Jeghers syndrome (Clinvar variation ID: 254654). Multiple different amino acid substitutions occurring at this position, p.Asn181Lys, p.Asn181Glu, p.Asn181Thr, p.Asn181Ile, have been reported in individuals affected with Peutz-Jeghers syndrome, indicating that asparagine at this position is important for STK11 protein function (PMID: 9887330, 15863673, 30689838; Clinvar variation ID: 428757). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 24, 2020	The p.N181S pathogenic mutation (also known as c.542A>G), located in coding exon 4 of the STK11 gene, results from an A to G substitution at nucleotide position 542. The asparagine at codon 181 is replaced by serine, an amino acid with highly similar properties. This alteration was identified in two first-degree relatives from a family suspected of having Peutz-Jeghers syndrome (Ambry internal data). Based on an internal structural assessment, this alteration disrupts the Mg-ATP binding in the active site of STK11 (Zeqiraj E et al. Science. 2009 Dec;326:1707-11; Gerlits O et al. Biochemistry. 2013 May;52:3721-7). Other alterations at the same codon (p.N181K, p.N181Y, p.N181T, p.N181E) have also been identified in individuals either diagnosed with or suspected to have Peutz-Jeghers syndrome (Ambry internal data; Ylikorkala A et al. Hum. Mol. Genet. 1999 Jan;8:45-51; Connolly DC et al. Am. J. Pathol. 2000 Jan;156:339-45; Amos CI et al. J. Med. Genet. 2004 May;41:327-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;D;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.0	.;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.96		Gain of disorder (P = 0.0598);Gain of disorder (P = 0.0598);.;
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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

Other links and lift over

dbSNP: rs886037859; hg19: chr19-1220449; COSMIC: COSV58823816; COSMIC: COSV58823816;