rs778376925

Positions:

• chr19-1207093-C-A
• chr19-1207093-C-G
• chr19-1207093-C-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.180C>A​(p.Tyr60*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.100

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 19-1207093-C-A is Pathogenic according to our data. Variant chr19-1207093-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 428750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.180C>A	p.Tyr60*	stop_gained	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.180C>A	p.Tyr60*	stop_gained	1/9		NP_001394184.1
STK11	NR_176325.1	n.1316C>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.180C>A	p.Tyr60*	stop_gained	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.180C>A	p.Tyr60*	stop_gained	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11324C>A		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.180C>A		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

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	Feb 21, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428750). This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9428765, 16287113, 17026623). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr60*) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2021

The p.Y60* pathogenic mutation (also known as c.180C>A), located in coding exon 1 of the STK11 gene, results from a C to A substitution at nucleotide position 180. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This alteration has been reported in multiple patients with clinical diagnoses of Peutz-Jeghers syndrome (Wang ZJ et al. J Med Genet, 1999 May;36:365-8; Lim W et al. Br J Cancer, 2003 Jul;89:308-13; Chow E et al. Clin Genet, 2006 Nov;70:409-14; Papp J et al. BMC Med Genet, 2010 Nov;11:169; Baynam G et al. BMJ Case Rep, 2011 Sep;2011:). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.67	D
Vest4		0.87
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs778376925; hg19: chr19-1207092; COSMIC: COSV58821737; COSMIC: COSV58821737;