rs587782424

Variant names:

• chr19-1219345-CGT-C
• rs587782424
• NM_000455.5:c.402_403delTG

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.402_403delTG​(p.Cys134TrpfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C134C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.70
• 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 19-1219345-CGT-C is Pathogenic according to our data. Variant chr19-1219345-CGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 182913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.402_403delTG	p.Cys134TrpfsTer28	frameshift_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.402_403delTG	p.Cys134TrpfsTer28	frameshift_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1669_1670delTG		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.402_403delTG	p.Cys134TrpfsTer28	frameshift_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.402_403delTG	p.Cys134TrpfsTer28	frameshift_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.30_31delTG	p.Cys10TrpfsTer28	frameshift_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*227_*228delTG		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*227_*228delTG		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys134Trpfs*28) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 20393878). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 182913). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 20, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The presence of the c.402_403delTG mutation was confirmed in the submitted specimen. The c.402_403delTG mutation in the STK11 gene causes a frameshift starting with codon Cysteine 134, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Cys134TrpfsX28. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense mediated mRNA decay. Although this mutation has not been previously reported to our knowledge. The variant is found in STK11 panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587782424; hg19: chr19-1219344; COSMIC: COSV58823734; COSMIC: COSV58823734;