19-1207065-TGGG-TGGGGG

Variant names:

• chr19-1207065-T-TGG
• rs1131690917
• NM_000455.5:c.156_157dupGG

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.156_157dupGG​(p.Asp53GlyfsTer12) 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. D53D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.65
• Publications: 1 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 19-1207065-T-TGG is Pathogenic according to our data. Variant chr19-1207065-T-TGG is described in ClinVar as Pathogenic. ClinVar VariationId is 1775237.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.156_157dupGG	p.Asp53GlyfsTer12	frameshift	Exon 1 of 10	NP_000446.1
	STK11	NM_001407255.1		c.156_157dupGG	p.Asp53GlyfsTer12	frameshift	Exon 1 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1292_1293dupGG		non_coding_transcript_exon	Exon 1 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.156_157dupGG	p.Asp53GlyfsTer12	frameshift	Exon 1 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.156_157dupGG	p.Asp53GlyfsTer12	frameshift	Exon 1 of 9	ENSP00000498804.1
	STK11	ENST00000593219.6	TSL:3	n.156_157dupGG		non_coding_transcript_exon	Exon 1 of 11	ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 15, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.156_157dupGG pathogenic mutation, located in coding exon 1 of the STK11 gene, results from a duplication of GG at nucleotide position 156, causing a translational frameshift with a predicted alternate stop codon (p.D53Gfs*12). This mutation (designated as 157-158insGG) has been identified in an individual satisfying clinical diagnostic criteria for Peutz-Jeghers syndrome (Amos CI et al. J Med Genet, 2004 May;41:327-33). 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 09, 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 frameshift predicted to result in premature protein truncation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1131690917; hg19: chr19-1207064;