rs864622488

chr19-1222987-G-Achr19-1222987-G-Cchr19-1222987-G-T

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.923G>A(p.Trp308Ter) variant causes a stop gained, splice region 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 stop_gained, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.60

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 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 19-1222987-G-A is Pathogenic according to our data. Variant chr19-1222987-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1222987-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.923G>A	p.Trp308Ter	stop_gained, splice_region_variant	8/10	ENST00000326873.12
STK11	NM_001407255.1	c.923G>A	p.Trp308Ter	stop_gained, splice_region_variant	8/9
STK11	NR_176325.1	n.2190G>A		splice_region_variant, non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.923G>A	p.Trp308Ter	stop_gained, splice_region_variant	8/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2023	The p.W308* pathogenic mutation (also known as c.923G>A), located in coding exon 8 of the STK11 gene, results from a G to A substitution at nucleotide position 923. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with STK11-related disease (Ylikorkala A et al. Hum Mol Genet, 1999 Jan;8:45-51; Chiang JM et al. Asian J Surg, 2018 Sep;41:480-485; Wu BD et al. Biomed Res Int, 2020 May;2020:9159315; Ambry internal data). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 26, 2021	This variant changes 1 nucleotide in exon 8 of the STK11 gene, creating a premature translation stop signal at codon 308 of the STK11 protein. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Peutz–Jeghers polyposis syndrome (PMID: 9887330, 20497868, 28869103, 30092773). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of STK11 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Peutz-Jeghers syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 28, 2022	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 create or strengthen a splice site. This sequence change creates a premature translational stop signal (p.Trp308*) 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 variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9887330, 28869103, 32462036). ClinVar contains an entry for this variant (Variation ID: 492567). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Aug 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	55
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.83
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622488; hg19: chr19-1222986;