Variant classification summary

NM_012289.4:c.1639G>A

KEAP1 · NP_036421.2:p.(Val547Ile) · NM_012289.4

GRCh37: chr19:10599937 C>T · GRCh38: chr19:10489261 C>T

Gene: KEAP1 Transcript: NM_012289.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

KEAP1

Transcript

NM_012289.4

Protein

NP_036421.2:p.(Val547Ile)

gnomAD AF

2.169399076455822e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 allele frequency 2.17e-05, below the 0.1% population rarity threshold.

2

BP4 (Supporting): concordant benign-leaning predictions, REVEL 0.271 (<=0.290 threshold) and SpliceAI max delta 0.003 (below 0.2).

3

Synthesis: with only one supporting pathogenic and one supporting benign criterion, no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold is reached; overall classification is Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback: 1 PM (supporting) + 1 BP (supporting) does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule, so the variant is classified as 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	N/A	Not applicable: this is a missense change, and PVS1 applies only to null variants such as nonsense, frameshift, or canonical splice-site changes.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no other pathogenic variant producing the same p.Val547Ile change exists, as this variant is absent from ClinVar.	clinvar
PS2	Not assessed	Not assessed: no de novo occurrence was documented, with no parental testing showing the variant absent in both biological parents.
PS3	Not assessed	Not assessed: no functional assay data for p.Val547Ile (e.g., NRF2/ARE reporter activity) were available.
PS4	Not assessed	Not assessed: no case series, case-control comparison, or disease-enrichment data for this variant were available.
PM1	Not met	Not met: cancerhotspots.org reports no significant hotspot at residue 547, and COSMIC shows only a single somatic occurrence.	oncokb
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 2.17e-05, below the 0.1% rarity threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no observation of the variant in trans with a pathogenic variant in an affected individual was available.
PM4	N/A	Not applicable: the variant is missense, so no protein length change occurs for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 547 previously established as pathogenic was available for comparison.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no suspected de novo occurrence, with or without parental confirmation, was documented.
PP1	Not assessed	Not assessed: no family segregation data were available to evaluate cosegregation with disease.
PP2	Not assessed	Not assessed: no gene-level missense constraint metric (e.g., gnomAD missense Z-score) was available to establish PP2 eligibility.	oncokb
PP3	Not met	Not met: REVEL score 0.271 is below the >=0.644 supporting-pathogenic threshold, and SpliceAI max delta 0.003 is below 0.2.	spliceai revel
PP4	Not assessed	Not assessed: no patient phenotype or clinical presentation was provided.
PP5	Not met	Not met: the variant is absent from ClinVar, so no expert-panel pathogenic assertion exists to trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 2.17e-05 is far below the >1% stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest gnomAD allele frequency 7.69e-05 (South Asian) is below the >0.3% benign threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-carrier phenotype or disease-model evidence was available; gnomAD reports zero homozygotes.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal function of p.Val547Ile were available.
BS4	Not assessed	Not assessed: no unaffected relatives or non-segregation analysis were documented.
BP1	Not assessed	Not assessed: no data confirming or excluding missense as a disease mechanism for KEAP1 were available.
BP2	Not assessed	Not assessed: no phase-resolved genotypes or paired pathogenic variant were available to evaluate trans/cis configuration.
BP3	N/A	Not applicable: the variant is missense, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL score 0.271 is below the <=0.290 benign-supporting threshold, and SpliceAI max delta 0.003 is below 0.2.	spliceai revel
BP5	Not assessed	Not assessed: no phenotype or molecular finding indicating an alternative genetic cause was provided.
BP6	Not met	Not met: the variant is absent from ClinVar, so no expert-panel benign assertion exists to trigger BP6.	clinvar
BP7	N/A	Not applicable: the variant is missense and alters the protein sequence, while BP7 applies to synonymous variants.	generic_acmg_combination_rules

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