NM_012289.4:c.542_543insT

KEAP1 · NP_036421.2:p.(Ser182GlnfsTer11) · NM_012289.4

GRCh37: chr19:10610167 G>GA · GRCh38: chr19:10499491 G>GA

Gene: KEAP1 Transcript: NM_012289.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

KEAP1

Transcript

NM_012289.4

Protein

NP_036421.2:p.(Ser182GlnfsTer11)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

PM2 (supporting) is met: the variant is completely absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to nucleotide substitutions producing the same amino acid change as an established pathogenic missense variant. This variant is a frameshift insertion, not a nucleotide substitution.
PS2	Not met	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	Not assessed	OncoKB annotates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect based on curated literature. However, the three OncoKB-cited publications (PMID:17020408, PMID:24142871, PMID:24322982) discuss KEAP1 functional biology and somatic cancer mutations generally but do not mention NM_012289.4:c.542_543insT or provide variant-specific functional validation. No primary functional study demonstrating a damaging effect of this exact variant was identified.	oncokb
PS4	Not met	The variant has not been reported in affected individuals. No case reports, cohort studies, or ClinVar submissions document NM_012289.4:c.542_543insT in patients with a KEAP1-associated phenotype.
PS5	Not met	No established pathogenic variant at the same amino acid position has been identified for comparison. This is a frameshift variant, for which the PS5 framework (designed for missense substitutions) is not directly applicable.
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot as determined by Cancer Hotspots analysis. No ClinGen- or VCEP-defined critical functional domain applies to KEAP1 under the generic ACMG framework, and no domain-level PM1 assignment was identified.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	Skipped per case instructions.
PM4	N/A	PM4 applies to non-frameshift protein length changes (in-frame deletions/insertions in nonrepeat regions or stop-loss variants). NM_012289.4:c.542_543insT is a frameshift insertion covered by PVS1; applying PM4 would double-count the same molecular evidence.
PM5	N/A	Unable to confirm classic same-residue PM5 semantics for a frameshift insertion. No same-residue comparator variants identified in ClinVar or via automated candidate harvesting.
PM6	Not met	No presumed de novo occurrence (without confirmed maternity and paternity) has been reported for this variant.
PP1	Not met	No cosegregation data with disease in multiple affected family members is available. KEAP1 is not a well-characterized Mendelian gene with documented family-based linkage studies for this variant.
PP2	N/A	PP2 applies to genes where missense variants are a common disease mechanism with a low rate of benign missense variation. KEAP1 is not established as such a gene, and this variant is a frameshift, not a missense.
PP3	Not assessed	SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion variants. HCI Prior is not available for KEAP1. Without multiple lines of computational evidence supporting a deleterious effect, PP3 cannot be applied for this insertion variant.	spliceai
PP4	Not met	No affected individuals with this variant and specific phenotype data have been reported. The variant's phenotype specificity cannot be assessed.
PP5	Not met	No reputable clinical laboratory or diagnostic source has reported NM_012289.4:c.542_543insT as pathogenic. The variant is absent from ClinVar.
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%). BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%). BS1 requires an allele frequency >0.3% in population databases.	gnomad_v2 gnomad_v4
BS2	Not met	The variant has not been observed in healthy adult individuals. Its complete absence from gnomAD means no observation in presumed healthy population controls has been documented.
BS3	Not assessed	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. Full-text was not available for verification. OncoKB annotation of Likely Loss-of-function is inconsistent with benign functional evidence. No variant-specific functional studies demonstrating no damaging effect were identified.
BS4	Not met	No evidence of non-segregation with disease in affected family members. No family studies are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where a different missense mechanism causes disease and truncating variants are the predominant pathogenic mechanism. NM_012289.4:c.542_543insT is a frameshift truncating variant, not a missense variant.
BP2	Not met	No observation of this variant in cis with a known pathogenic KEAP1 variant has been reported. No phase information is available from public databases or literature.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_012289.4:c.542_543insT is a frameshift insertion, not an in-frame variant.
BP4	Not assessed	SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion variants. Without multiple lines of computational evidence predicting no impact, BP4 cannot be applied for this frameshift insertion variant.	spliceai
BP5	Not met	No case has been reported where an alternative molecular basis for disease was identified in an individual harboring this variant. No clinical case data is available.
BP6	Not met	No reputable source has reported NM_012289.4:c.542_543insT as benign. The variant is absent from ClinVar.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_012289.4:c.542_543insT is a frameshift insertion, not a synonymous variant.

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