19-1207022-C-T

Position:

• chr19-1207022-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000455.5(STK11):​c.109C>T​(p.Gln37*) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.68

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1207022-C-T is Pathogenic according to our data. Variant chr19-1207022-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 376334.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.109C>T	p.Gln37*	stop_gained	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.109C>T	p.Gln37*	stop_gained	1/9		NP_001394184.1
STK11	NR_176325.1	n.1245C>T		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.109C>T	p.Gln37*	stop_gained	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.109C>T	p.Gln37*	stop_gained	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11395C>T		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.109C>T		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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	Myriad Genetics, Inc.	Feb 09, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 13, 2017	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in STK11 are known to be pathogenic. This particular variant has been reported in the literature in at least one individual with Peutz-Jeghers syndrome (PMID: 15188174). This sequence change creates a premature translational stop signal at codon 37 (p.Gln37*) of the STK11 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15188174, 16707622, 30528796, 24998845) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2021

The p.Q37* pathogenic mutation (also known as c.109C>T), located in coding exon 1 of the STK11 gene, results from a C to T substitution at nucleotide position 109. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation has been reported in multiple individuals fulfilling criteria for a clinical diagnosis of Peutz-Jeghers syndrome (PJS) (Lim W et al. Gastroenterology. 2004 Jun;126(7):1788-94; Hearle N et al. Clin Cancer Res. 2006 May 15;12(10):3209-15; Jiang YL et al. Cancer Genet, 2019 01;230:47-57). In addition, in vivo functional studies demonstrate that this alteration confers tumorigenicity (Dahmani R et al. Oncogene, 2015 Apr;34:2337-46). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.89
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs121913324; hg19: chr19-1207021; COSMIC: COSV58819862; COSMIC: COSV58819862;