chr19-1207093-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.100
Variant links:
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]

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ACMG classification

Classification made for transcript

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
STK11NM_000455.5 linkuse as main transcriptc.180C>A p.Tyr60* stop_gained 1/10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NM_001407255.1 linkuse as main transcriptc.180C>A p.Tyr60* stop_gained 1/9 NP_001394184.1
STK11NR_176325.1 linkuse as main transcriptn.1316C>A non_coding_transcript_exon_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.180C>A p.Tyr60* stop_gained 1/101 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000652231.1 linkuse as main transcriptc.180C>A p.Tyr60* stop_gained 1/9 ENSP00000498804.1 Q15831-2
STK11ENST00000585748.3 linkuse as main transcriptc.-82-11324C>A intron_variant 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.5 linkuse as main transcriptn.180C>A non_coding_transcript_exon_variant 1/43 ENSP00000466610.1 K7EMR0

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
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 21, 2022For 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 submitterclinical testingAmbry GeneticsJun 28, 2021The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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