19-1221264-GTTGT-G

Position:

• chr19-1221264-GTTGT-G

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.790_793delTTTG​(p.Phe264fs) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.73

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 19-1221264-GTTGT-G is Pathogenic according to our data. Variant chr19-1221264-GTTGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 372523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1221264-GTTGT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.790_793delTTTG	p.Phe264fs	frameshift_variant	6/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.790_793delTTTG	p.Phe264fs	frameshift_variant	6/9		NP_001394184.1
STK11	NR_176325.1	n.2057_2060delTTTG		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.790_793delTTTG	p.Phe264fs	frameshift_variant	6/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.790_793delTTTG	p.Phe264fs	frameshift_variant	6/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.418_421delTTTG	p.Phe140fs	frameshift_variant	8/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

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 12, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372523). This variant is also known as c.787del4. This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9809980, 15863673, 16287113, 17010210, 23718779, 26979979). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe264Argfs*22) 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	Frameshift 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12552571, 9809980, 16287113, 23718779, 17404884, 19727776, 17010210, 25742471, 11103790, 15863673) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.790_793delTTTG pathogenic mutation, located in coding exon 6 of the STK11 gene, results from a deletion of 4 nucleotides at nucleotide positions 790 to 793, causing a translational frameshift with a predicted alternate stop codon (p.F264Rfs*22). This alteration has been identified in multiple cohorts of patients with a clinical diagnosis of Peutz-Jegher syndrome (Resta N et al. Cancer Res. 1998 Nov;58:4799-801; Schumacher V et al. J. Med. Genet. 2005 May;42:428-35; Thakur N et al. BMC Med. Genet. 2006 Sep;7:73; Jiang YL et al. Cancer Genet. 2019 01;230:47-57). Of note, this alteration is also designated as 787del4 in the published 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913320; hg19: chr19-1221263;