rs121913320

chr19-1221264-GTTGT-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000455.5(STK11):c.790_793del(p.Phe264ArgfsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L263L) has been classified as Likely benign. 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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	UniProt
STK11	NM_000455.5	c.790_793del	p.Phe264ArgfsTer22	frameshift_variant	6/10	ENST00000326873.12
STK11	NM_001407255.1	c.790_793del	p.Phe264ArgfsTer22	frameshift_variant	6/9
STK11	NR_176325.1	n.2057_2060del		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.790_793del	p.Phe264ArgfsTer22	frameshift_variant	6/10	1	NM_000455.5	P1

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	Invitae	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	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2017	- -

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;