PVS1 (very strong) is met: NM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6 creating a premature termination codon at position 192 (NP_036421.2:p.(Ser182GlnfsTer11)), predicted to trigger nonsense-mediated decay. KEAP1 loss of function is an established germline disease mechanism, supported by published pathogenic frameshift variants causing familial multinodular goiter (PMID:39373520).1 PM2 (supporting) is met: the variant is completely absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.2 No additional pathogenic criteria are met. The variant has not been reported in affected individuals (PS4 not met), no functional studies are available for this exact variant (PS3 not assessed), no de novo observations exist (PS2/PM6 not met), and no segregation or case-level data is available (PP1/PP4 not met). No benign criteria are met. The variant is absent from population databases (BA1/BS1 not met), and no functional or clinical evidence supports a benign interpretation.3 Under generic ACMG/AMP 2015 combination rules (PMID:25741868), PVS1 (very strong) + PM2 (supporting) does not reach a Likely Pathogenic or Pathogenic threshold. The minimum requirement for Likely Pathogenic with PVS1 is one additional moderate criterion, which is not met. The classification is therefore Variant of Uncertain Significance (VUS).4
KEAP1
Final classification
VUS
KEAP1 c.542_543insT · p.Ser182GlnfsTer11
KEAP1
PVS1 (very strong) is met: NM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6 creating a premature termination codon at position 192 (NP_036421.2:p.(Ser182GlnfsTer11)), predicted to trigger nonsense-mediated decay. KEAP1 loss of function is an established germline disease mechanism, supported by published pathogenic frameshift variants causing familial multinodular goiter (PMID:39373520).
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
KEAP1 c.542_543insT
PVS1 + PM2
→
VUS
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
4
generic_acmg_combination_rules
Gene diagram
· NM_012289.4 · variants mapped to exon structure
KEAP1
NM_012289.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6, predicted to cause premature termination at codon 192 (NP_036421.2:p.(Ser182GlnfsTer11)), well upstream of the last exon and expected to trigger nonsense-mediated decay. KEAP1 loss of function is an established disease mechanism supported by germline literature (PMID:39373520 identifies pathogenic germline KEAP1 mutations including p.V411fs causing familial multinodular goiter). Under ClinGen SVI PVS1 recommendations (PMC6185798), this frameshift null variant meets PVS1 at very strong strength.
Frameshift insertion (c.542_543insT) creating premature termination codon at position 192 of 625 amino acidsNMD predicted (PTC in exon 2 of 6well upstream of the last exon-exon junction)
✓
PM2
supporting
Pathogenic
NM_012289.4:c.542_543insT is absent from gnomAD v2.1 and v4.1, meeting the PM2 threshold of allele frequency <0.1% in population databases. Complete absence from large, diverse population cohorts supports pathogenicity.
Absent from gnomAD v2.1 (0 alleles observed)Absent from gnomAD v4.1 (0 alleles observed)
Assessed · not applied
Pathogenic
PS2
No de novo observation with confirmed maternity and paternity has been reported for NM_012289.4:c.542_543insT in the literature or ClinVar.
PS3
OncoKB annotates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect based on curated literature.
PS4
The variant has not been reported in affected individuals.
PM1
The variant does not lie within a statistically significant mutational hotspot as determined by Cancer Hotspots analysis.
PM6
No presumed de novo occurrence (without confirmed maternity and paternity) has been reported for this variant.
PP1
No cosegregation data with disease in multiple affected family members is available.
PP3
SpliceAI predicts no splice impact (max delta score = 0.00).
PP4
No affected individuals with this variant and specific phenotype data have been reported.
PP5
No reputable clinical laboratory or diagnostic source has reported NM_012289.4:c.542_543insT as pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%).
BS1
The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%).
BS2
The variant has not been observed in healthy adult individuals.
BS3
The three OncoKB-cited publications (PMID:17020408, PMID:24142871, PMID:24322982) discuss KEAP1 functional biology and somatic cancer mutations but do not mention NM_012289.4:c.542_543insT in their abstracts.
BS4
No evidence of non-segregation with disease in affected family members.
BP2
No observation of this variant in cis with a known pathogenic KEAP1 variant has been reported.
BP4
SpliceAI predicts no splice impact (max delta score = 0.00).
BP5
No case has been reported where an alternative molecular basis for disease was identified in an individual harboring this variant.
BP6
No reputable source has reported NM_012289.4:c.542_543insT as benign.
N/A · 8
PS1 · 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
This variant is absent from gnomAD-Canada.
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 = 0.00).
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.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & References.
PMID 39373520
Found
Frameshift insertion (c.542_543insT) creating premature termination codon at position 192 of 625 amino acids NMD predicted (PTC in exon 2 of 6 well upstream of the last exon-exon junction) KEAP1 germline loss-of-function mechanism supported by published pathogenic frameshift variants (PMID:39373520: p.V411fs in familial multinodular goiter)
Applied to
→PVS1 supports · met
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment