rs1057520042

Variant names:

• chr19-1222988-G-A
• rs1057520042
• NM_000455.5:c.924G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1222988-G-A
• chr19-1222988-G-C
• chr19-1222988-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000455.5(STK11):​c.924G>A​(p.Trp308*) 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: 33)
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.60
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• familial pancreatic carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Peutz-Jeghers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 19-1222988-G-A is Pathogenic according to our data. Variant chr19-1222988-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3231752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.924G>A	p.Trp308*	stop_gained	Exon 8 of 10	NP_000446.1
	STK11	NM_001407255.1		c.924G>A	p.Trp308*	stop_gained	Exon 8 of 9	NP_001394184.1
	STK11	NR_176325.1		n.2191G>A		non_coding_transcript_exon	Exon 9 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.924G>A	p.Trp308*	stop_gained	Exon 8 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.924G>A	p.Trp308*	stop_gained	Exon 8 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.552G>A	p.Trp184*	stop_gained	Exon 10 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 06, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W308* pathogenic mutation (also known as c.924G>A), located in coding exon 8 of the STK11 gene, results from a G to A substitution at nucleotide position 924. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This mutation has been reported in several individuals with clinical diagnoses or features of Peutz-Jeghers syndrome (PJS) (Resta N et al. Dig Liver Dis, 2013 Jul;45:606-11; Jiang YL et al. BMC Med Genet, 2018 Aug;19:141; Liu Q et al. Diagn Pathol, 2022 Dec;17:96). 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

Jan 10, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria was used: PVS1; PM2_SUP; PS4_SUP

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	46
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		9.6
Vest4		0.83
GERP RS		2.5
PromoterAI		-0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1057520042; hg19: chr19-1222987; COSMIC: COSV58824598;