NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 producing p.(Lys44SerfsTer3), predicted to trigger nonsense-mediated decay and complete loss of STK11 protein expression. STK11 loss of function is a well-established mechanism for Peutz-Jeghers syndrome (autosomal dominant).1 This variant is absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.2 The variant has not been reported in ClinVar, COSMIC, or any published patient cohort evaluated in this assessment.3 No variant-specific functional studies, segregation data, or de novo observations were identified in the literature. Five OncoKB-curated STK11 publications were reviewed; none mention this variant.4 Applying generic ACMG/AMP 2015 classification rules (PMID:25741868): PVS1 (very_strong) + PM2 (moderate) meets the Likely Pathogenic combination threshold (1 Very Strong + 1 Moderate).5
STK11
Final classification
Likely Pathogenic
PVS1PM2
STK11
c.129_141del
p.Lys44SerfsTer3
This variant
NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 producing p.(Lys44SerfsTer3), predicted to trigger nonsense-mediated decay and complete loss of STK11 protein expression. STK11 loss of function is a well-established mechanism for Peutz-Jeghers syndrome (autosomal dominant).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
STK11 c.129_141del
PVS1 + PM2
→
Likely Pathogenic
Gene diagram
· NM_000455.5 · variants mapped to exon structure
STK11
NM_000455.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 (of 9 coding exons) resulting in p.(Lys44SerfsTer3). STK11 loss of function is a well-established disease mechanism for Peutz-Jeghers syndrome (autosomal dominant). The premature termination codon at position 46 occurs well before the last exon-exon junction and is predicted to trigger nonsense-mediated decay, leading to complete absence of the STK11 protein product. Under ClinGen SVI PVS1 recommendations (PMC6185798), full-strength PVS1 is applicable.
Frameshift (13bp deletion) in exon 1/9 of STK11a tumor suppressor gene with established LOF mechanism in Peutz-Jeghers syndromePremature termination at codon 46 predicted to trigger NMD (PTC well upstream of last exon-exon junction)
✓
PM2
moderate
Pathogenic
NM_000455.5:c.129_141del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), consistent with a rare pathogenic variant. Under generic ACMG/AMP rules, absence from large population databases supports a pathogenic interpretation (PM2).
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)
Assessed · not applied
· 8 not met · 9 not assessed
Pathogenic
PS2
No de novo observation has been reported for NM_000455.5:c.129_141del.
PS3
No variant-specific functional studies were identified for NM_000455.5:c.129_141del in the literature.
PS4
No case-control or prevalence data are available for this variant.
PM1
The variant at codon 44 is located N-terminal to the STK11 kinase domain (approximately residues 49-309).
PM6
No de novo observation has been reported for this variant.
PP1
No cosegregation data are available for this variant.
PP4
No patient phenotype or family history data were provided for clinical correlation.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
NM_000455.5:c.129_141del is absent from gnomAD v2.1 and v4.1.
BS1
NM_000455.5:c.129_141del is absent from gnomAD v2.1 and v4.1.
BS2
No observation of this variant in healthy adult individuals has been reported.
BS3
No variant-specific functional studies demonstrating a benign effect are available for NM_000455.5:c.129_141del.
BS4
No family segregation data are available to evaluate lack of segregation with disease.
BP2
No data on observation of this variant in trans with a pathogenic STK11 variant or in cis with a pathogenic variant are available.
BP4
Computational evidence does not support a benign interpretation.
BP5
No data identifying an alternate molecular basis for disease in a patient carrying this variant are available.
BP6
No reputable source has reported this variant as benign.
N/A · 8
PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
19892943 ↗
Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation.
ONCOKB
24652667 ↗
STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome.
ONCOKB