NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC is a frameshift variant predicted to cause p.(Gly180ValfsTer102) with a premature termination codon at residue 281, expected to trigger nonsense-mediated decay. Loss of function is an established disease mechanism for STK11 in Peutz-Jeghers syndrome.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting its rarity in the general population.2 The variant is absent from ClinVar and has not been reported in affected individuals, in somatic cancer databases (COSMIC), or in any of the five gene-level functional publications reviewed.3 No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified. Five publications retrieved via OncoKB discuss STK11 function at the gene level but none include NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC. Under the ClinGen SVI PVS1 decision framework (PMC6185798), a frameshift variant upstream of the last exon in a gene with an established loss-of-function disease mechanism qualifies for PVS1 at full strength.4
STK11
Final classification
VUS
STK11 c.539_571delinsTGGTAGGGTGGCACCTC · p.Gly180ValfsTer102
STK11
NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC is a frameshift variant predicted to cause p.(Gly180ValfsTer102) with a premature termination codon at residue 281, expected to trigger nonsense-mediated decay. Loss of function is an established disease mechanism for STK11 in Peutz-Jeghers syndrome.
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 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
STK11 c.539_571delinsTGGTAGGGTGGCACCTC
PVS1 + PM2
→
VUS
1
pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗
Gene diagram
· NM_000455.4 · variants mapped to exon structure
STK11
NM_000455.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Frameshift variant NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC predicts p.(Gly180ValfsTer102), introducing a premature termination codon at residue 281 within exon 4 of 9 coding exons. Loss of function is a well-established disease mechanism for STK11 in Peutz-Jeghers syndrome. The predicted transcript is expected to undergo nonsense-mediated decay per the ClinGen SVI PVS1 decision framework (PMC6185798).
Frameshift variant in exon 4 of 9 coding exonsLoss of function is established disease mechanism for STK11 (Peutz-Jeghers syndrome)PTC at residue 281 predicted to trigger nonsense-mediated decay
✓
PM2
supporting
Pathogenic
NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, indicating it is not observed in large population cohorts.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo observation has been reported for NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC in any reviewed publication or database.
PS3
No variant-specific functional studies were identified for NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC.
PS4
The variant is absent from ClinVar and has not been observed in affected individuals in any reviewed source.
PM6
No de novo observation has been reported for this variant in any reviewed publication or database.
PP1
No segregation data are available for this variant.
PP3
In silico tools applicable to indels are limited.
PP4
No phenotype or family history data specific to this variant are available.
PP5
The variant is absent from ClinVar.
Benign
BA1
Allele frequency is 0% across all gnomAD datasets, well below the BA1 threshold of >1%.
BS1
Allele frequency is 0% across all gnomAD datasets, well below the BS1 threshold of >0.3%.
BS2
The variant has not been observed in any healthy adult control population.
BS3
No variant-specific functional studies were identified demonstrating no deleterious effect for NM_000455.4:c.539_571delinsTGGTAGGGTGGCACCTC.
BS4
No segregation or non-segregation data are available.
BP2
No observation of this variant in trans with a known pathogenic STK11 variant has been reported.
BP4
Multiple lines of computational evidence do not suggest a benign effect.
BP5
No observation of this variant in a case where an alternate molecular basis for disease has been identified.
BP6
No reputable source has classified this variant as benign.
N/A · 9
PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
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 possible splice impact for this variant (max delta score = 0.47).
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