rs121913315

Positions:

• chr19-1220488-G-A
• chr19-1220488-G-C
• chr19-1220488-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.580G>A​(p.Asp194Asn) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D194E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a mutagenesis_site Loss of kinase activity. (size 0) in uniprot entity STK11_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220490-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-1220488-G-A is Pathogenic according to our data. Variant chr19-1220488-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1220488-G-A is described in Lovd as [Pathogenic]. Variant chr19-1220488-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.580G>A	p.Asp194Asn	missense_variant	4/10	ENST00000326873.12
STK11	NM_001407255.1	c.580G>A	p.Asp194Asn	missense_variant	4/9
STK11	NR_176325.1	n.1847G>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.580G>A	p.Asp194Asn	missense_variant	4/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453076 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a substitution of aspartic acid with asparagine at position 194 of the STK11 protein. This particular aspartic acid is highly conserved and there is small physicochemical variation caused by the change. The mutation is absent from population databases but it is reported in literature in individual or families affected by colorectal cancer and the Peutz-Jeghers syndrome (PMID:23399955, PMID: 10408777, PMID: 16582077). The mutation is located in a region of the protein that is considered to be particularly important for its proper function thus the mutation frequency in this region is high, thus it is considered a mutational 'hotspot' region (PMID: 14976552, PMID:14517248, PMID:21189378, PMID:23240097). The mutation database ClinVar contains entries for this variant (Variation ID: 188348). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2019	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32462036, 31159747, 28152038, 16287113, 20393878, 26233267, 25226294, 10408777, 23718779, 15863673, 17026623, 26056085, 27081308, 12865922, 23430953, 20435009, 16582077, 17924967, 23399955, 30528796) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 15, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/252614 chr). Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. One de novo case with parental identity confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The STK11 p.Asp194Asn variant was identified in 18 of 1868 proband chromosomes (frequency: 0.01) from individuals or families with Peutz-Jeghers Syndrome and is consistently reported as pathogenic in the literature (Aretz 2005, Borun 2013, Chow 2006, Crocker 2014, De Rosa 2010, Hearle 2006, Lim 2003, Ngeow 2013, Schumacher 2005, Westerman 1999, de Leng 2007, Yang 2010). The variant was also identified in dbSNP (ID: rs121913315) as “With Pathogenic allele”, in ClinVar (as pathogenic by Invitae and EGL Diagnostics and as likely pathogenic by Ambry Genetics), Clinvitae (5x), Cosmic (seen in prostate, breast, small intestine, and lung cancer), LOVD 3.0 (as pathogenic), and Zhejiang University Database (8x as pathogenic). The variant was not identified in MutDB or Insight Hereditary Tumors Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Asp194 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Asparagine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Peutz-Jeghers syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 194 of the STK11 protein (p.Asp194Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Peutz-Jeghers syndrome (PJS) (PMID: 10408777, 12865922, 16287113, 16582077, 17026623, 20435009, 23399955, 23718779, 25226294). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188348). 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 expected to disrupt STK11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 12, 2024	This variant is considered pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 15561763]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10408777, 12865922, 16287113, 20393878]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2021	This missense variant replaces aspartic acid with asparagine at codon 194 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 reported for this variant, however other variants at this Asp194 position have been shown to be impaired or deficient in kinase activity (PMID: 11297520, 19414597, 32647375). This variant has been reported in individuals affected with Peutz-Jeghers syndrome and gastrointestinal polyposis (PMID: 10408777, 15188174, 15863673, 16287113, 16582077, 16707622, 17026623, 20393878, 20435009, 23415580, 23718779). 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	Jun 23, 2021	The p.D194N pathogenic mutation (also known as c.580G>A), located in coding exon 4 of the STK11 gene, results from a G to A substitution at nucleotide position 580. The aspartic acid at codon 194 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been described in multiple families meeting clinical diagnostic criteria for Peutz-Jeghers syndrome (PJS) (Westerman AM et al. Hum. Mutat. 1999;13:476-81; Schumacher V et al. J. Med. Genet. 2005 May;42:428-35; Chow E et al. Clin. Genet. 2006 Nov;70:409-14; Borun P et al. BMC Med. Genet. 2013 May;14:58; Hearle NC et al. J. Med. Genet. 2006 Apr;43:e15; Lim W et al. Br. J. Cancer. 2003 Jul;89:308-13; Jiang YL et al. Cancer Genet. 2019 01;230:47-57). This alteration has also been reported in two unrelated individuals with juvenile, adenomatous, and hyperplastic polyps (Ngeow J et al. Gastroenterology. 2013 Jun;144:1402-9, 1409.e1-5). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). Based on internal structural analysis using published crystal structures, D194N results in disruption of the ATP-binding active site (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;D;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.0	.;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		1.0
MutPred		0.98		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
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: rs121913315; hg19: chr19-1220487; COSMIC: COSV58820976; COSMIC: COSV58820976;