NM_012289.4:c.340G>A

KEAP1 · NP_036421.2:p.(Gly114Arg) · NM_012289.4

GRCh37: chr19:10610370 C>T · GRCh38: chr19:10499694 C>T

Gene: KEAP1 Transcript: NM_012289.4

Final call

VUS

PM2 supporting

Variant details

Gene

KEAP1

Transcript

NM_012289.4

Protein

NP_036421.2:p.(Gly114Arg)

gnomAD AF

6.195188073519536e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): gnomAD v4.1 total allele frequency 0.00006% (1/1,614,156 alleles, 0 homozygotes) is far below the 0.1% threshold.

Synthesis: with PM2 supporting as the only applied criterion, no ACMG/AMP 2015 Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule is satisfied, so the variant is classified as Variant of Uncertain Significance (VUS).

Final determination: Under the generic ACMG/AMP 2015 fallback combination rules (Richards et al. 2015, PMID:25741868), the sole applied criterion PM2 (supporting) does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold, 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	N/A	Not applicable: this is a missense change (p.Gly114Arg), and PVS1 applies only to null variants such as nonsense or frameshift.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same amino-acid change (p.Gly114Arg) was available to compare against.	clinvar pm5_candidates generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband genotype, parental-testing results, or family-history data were available to evaluate a confirmed de novo occurrence.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional studies of this variant were available; in-silico scores (REVEL 0.6, BayesDel 0.171) are not functional evidence.	oncokb generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data exist for this variant, which is unreported in ClinVar and COSMIC.
PM1	Not met	Not met: the variant is not in a statistically significant hotspot (Cancer Hotspots no-result), and no critical-domain rule applies to Gly114.	generic_acmg_combination_rules
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency 0.00006% is far below the 0.1% threshold, with zero homozygotes.	gnomad_v4 gnomad_v2 gnomad_canada clinvar pvs1_gene_context generic_acmg_combination_rules
PM3	N/A	Not applicable: KEAP1 germline disease is autosomal dominant, so the recessive-disorder in-trans requirement of PM3 does not apply.	generic_acmg_combination_rules pvs1_gene_context clinvar
PM4	N/A	Not applicable: this missense substitution does not alter protein length, so in-frame insertion/deletion and stop-loss rules do not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate pathogenic missense at residue Gly114 was available to establish that a different change at this residue is pathogenic.	clinvar pm5_candidates generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband or parental trio data were available, so an assumed de novo occurrence cannot be evaluated.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree, family-member genotypes, or segregation analysis were available for this variant.	clinvar generic_acmg_combination_rules
PP2	Not assessed	Not assessed: gene-level missense constraint metrics (e.g., gnomAD missense Z-score) were unavailable, even though missense is a known KEAP1 disease mechanism.	pvs1_gene_context oncokb generic_acmg_combination_rules
PP3	Not met	Not met: REVEL 0.600 is below the 0.644 supporting threshold, and SpliceAI 0.01 predicts no splice impact, so multiple deleterious lines are lacking.	revel bayesdel spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history was available, and no publication reports this exact variant.
PP5	Not met	Not met: ClinVar has no record of this variant, so no 3-star expert-panel pathogenic classification exists to apply.	clinvar
BA1	Not met	Not met: the highest observed allele frequency (0.00008%) is about four orders of magnitude below the 1% threshold.	gnomad_v4 gnomad_v2 gnomad_canada pvs1_gene_context generic_acmg_combination_rules
BS1	Not met	Not met: the highest allele frequency (0.00008%) is roughly four orders of magnitude below the 0.3% threshold for the disorder.	gnomad_v4 gnomad_v2 gnomad_canada pvs1_gene_context generic_acmg_combination_rules
BS2	Not met	Not met: only a single heterozygous exome carrier exists in gnomAD v4.1, far below any frequency supporting observation in healthy adults.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional studies demonstrating absence of a damaging effect on the protein were available for this variant.	oncokb spliceai revel bayesdel generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no affected family members were tested or reported, so non-segregation of the variant cannot be evaluated.	clinvar generic_acmg_combination_rules
BP1	Not met	Not met: pathogenic missense variants are established in KEAP1 germline disease, so a missense change cannot be discounted as benign by mechanism.	pvs1_gene_context generic_acmg_combination_rules
BP2	Not met	Not met: no trans or cis observation of this variant with a pathogenic variant has been reported.	generic_acmg_combination_rules clinvar gnomad_v4 pvs1_gene_context
BP3	N/A	Not applicable: this missense substitution does not involve an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only SpliceAI (delta 0.01) suggests no impact; REVEL 0.600 and BayesDel 0.171 do not, so multiple benign lines are lacking.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband case data or information about an alternate molecular basis for disease were available.
BP6	Not met	Not met: ClinVar has no record of this variant, so no 3-star expert-panel benign classification exists to apply.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, so the silent-variant premise of BP7 does not hold.	generic_acmg_combination_rules

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