19-1219358-C-T

Variant names:

• chr19-1219358-C-T
• rs730881970
• NM_000455.5:c.409C>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.409C>T​(p.Gln137*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.67

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.

• 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 19-1219358-C-T is Pathogenic according to our data. Variant chr19-1219358-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 182896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1219358-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.409C>T	p.Gln137*	stop_gained	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.409C>T	p.Gln137*	stop_gained	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1676C>T		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.409C>T	p.Gln137*	stop_gained	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.409C>T	p.Gln137*	stop_gained	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.37C>T	p.Gln13*	stop_gained	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*234C>T		downstream_gene_variant		3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1437676 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 713610

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.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 15, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q137* pathogenic mutation (also known as c.409C>T), located in coding exon 3 of the STK11 gene, results from a C to T substitution at nucleotide position 409. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This alteration was previously reported in three unrelated individuals with confirmed or suspected Peutz-Jegher syndrome (PJS) based on personal history of mucocutaneous hyperpigmentation and gastrointestinal polyps with or without a family history of PJS-related malignancies (Amos CI et al. J. Med. Genet. 2004 May;41:327-33). 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. -

Peutz-Jeghers syndrome Pathogenic:1

Feb 12, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.90, 0.91
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8

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: rs730881970; hg19: chr19-1219357; COSMIC: COSV58822821; COSMIC: COSV58822821;