KEAP1 c.1639G>A, p.(Val547Ile)

Reasoning

PM2 is met at supporting strength under the generic non-VCEP population rule used for this case. The variant is rare in large reference populations: gnomAD v2.1 AF 2.787e-05 (7/251166 alleles; 0 homozygotes) and gnomAD v4.1 AF 2.1694e-05 (35/1613350 alleles; 0 homozygotes), with the highest gnomAD v4.1 ancestry-specific AF 7.69079e-05 in South Asian individuals. All are below the generic PM2 rarity threshold of 0.1% (0.001). The variant is not completely absent, so this is rarity-based PM2 rather than strict absence-based PM2.

Rule

generic_non_vcep_population_threshold: PM2 supporting requires AF < 0.001

Evidence considered

• Generic non-VCEP PM2 threshold applied: AF <0.1% supports PM2.
• gnomAD v2.1: AF 2.787e-05, 7/251166 alleles, 0 homozygotes; highest South Asian AF 6.54236e-05.
• gnomAD v4.1: AF 2.1694e-05, 35/1613350 alleles, 0 homozygotes; highest South Asian AF 7.69079e-05.
• The variant is observed rather than absent in gnomAD; the conclusion therefore relies on the case's generic rarity threshold rather than a strict absent-from-controls formulation.

Still missing

• No KEAP1-specific VCEP/CSPEC PM2 rule or disease-specific maximum credible allele frequency was available.

Sources

Reasoning

No ClinGen VCEP specification is available for KEAP1, so generic ACMG/AMP BP4 rules apply. On the splice-impact path, SpliceAI predicts no significant splicing effect for NM_012289.4:c.1639G>A (max delta score = 0.003, all four delta scores <=0.003), well below the published SpliceAI threshold of 0.2 (Jaganathan et al. 2019, PMID 30661751) used to flag a possible splice-altering variant, consistent with a benign-supporting computational prediction. On the missense in-silico path, REVEL score = 0.271, which falls below the ClinGen SVI-calibrated REVEL BP4_Supporting threshold of <=0.290 (Pejaver et al., PMID 36413997), independently supporting a benign computational prediction for the p.(Val547Ile) substitution. Both independent lines of computational evidence concordantly support no deleterious effect; BP4 is applied at supporting strength (the two paths are not stacked to increase strength beyond supporting, consistent with standard ACMG/AMP combination rules).

Rule

generic_acmg_2015

Evidence considered

• SpliceAI (spliceailookup.broadinstitute.org) for NM_012289.4:c.1639G>A: max_delta_score=0.003, well below the >=0.2 threshold (Jaganathan et al., Cell 2019, PMID 30661751) for a predicted splice-altering effect -- supports no splicing impact.
• REVEL local predictor lookup: score = 0.271 for 19-10489261-C-T (GRCh38) -- below the ClinGen SVI-calibrated REVEL BP4_Supporting threshold of <=0.290 (Pejaver et al., PMID 36413997) -- supports a benign computational prediction for the missense change.

Still missing

• BayesDel score exists (-0.342965) but has no verified published calibration threshold usable by this pipeline; excluded from BP4 assessment despite being directionally consistent (more negative/benign-leaning).

Sources

Reasoning

PM1 requires the variant to lie in a well-established mutational hotspot or functional domain lacking benign variation. A cancerhotspots.org lookup for KEAP1 V547 returned no significant hotspot ('This variant does not lie in a statistically significant hotspot'). COSMIC shows only a single somatic occurrence (COSV50296072, n=1), which is not indicative of recurrent hotspot mutation. OncoKB has no variant-specific reviewed functional/oncogenic evidence for KEAP1 V547I (classification: 'Unknown Oncogenic Effect', not_reviewed=true). No CSPEC/VCEP-defined critical domain boundaries or missense-constraint (lack-of-benign-variation) data for the KEAP1 Kelch/DGR substrate-binding region were available in the case sources to support a domain-based PM1 call, so this cannot be confirmed as met from the available evidence.

Evidence considered

• cancerhotspots.org query for 'KEAP1 V547' returned search_status=no_result, found=false: 'This variant does not lie in a statistically significant hotspot.'
• COSMIC record COSV50296072 shows only 1 reported somatic occurrence for this exact variant, consistent with a non-recurrent site rather than a hotspot.
• OncoKB gene-level page for KEAP1 V547I shows no variant-specific reviewed evidence (classification 'Unknown Oncogenic Effect', is_variant_specific=false, not_reviewed=true); only generic gene-level context that KEAP1 is a tumor suppressor/adaptor protein recurrently mutated in lung cancer is provided, which does not establish residue-level domain criticality.

Still missing

• No VCEP/CSPEC-curated functional domain map or missense constraint (benign-variant depletion) data for KEAP1 was retrieved in this case bundle.
• COSMIC/hotspot evidence is limited to n=1 somatic occurrence, insufficient to establish a statistically validated hotspot.
• Structural/domain-criticality assessment of residue 547 was not sourced from a citable case evidence source.

Sources

Reasoning

No ClinGen VCEP specification is available for KEAP1 (vcep_materials.json: no cspec URL found; framework_mode = generic_acmg), so generic ACMG/AMP PP3 rules apply. This is a missense variant (NP_036421.2:p.(Val547Ile)). REVEL score = 0.271, which falls well below the ClinGen SVI-calibrated REVEL supporting-pathogenic threshold (>=0.644; Pejaver et al., PMID 36413997), so the missense in-silico path does not support PP3. On the splice-impact path, SpliceAI predicts no splicing effect (max delta score = 0.003; DS_AG 0.003, DS_AL 0.002, DS_DG 0.0, DS_DL 0.001), far below the published SpliceAI pathogenic-impact threshold of >=0.2 (Jaganathan et al. 2019, PMID 30661751), so splice prediction likewise does not support PP3. BayesDel score is present (-0.342965) but per pipeline policy no verified published threshold-to-ACMG-strength calibration is available for BayesDel, so it is treated as not_available and not used to support PP3. No computational evidence meets the threshold for pathogenic-supporting prediction.

Rule

generic_acmg_2015

Evidence considered

• SpliceAI (spliceailookup.broadinstitute.org) for NM_012289.4:c.1639G>A: DS_AG=0.003, DS_AL=0.002, DS_DG=0.0, DS_DL=0.001, max_delta_score=0.003 -- below the published >=0.2 threshold (Jaganathan et al., Cell 2019, PMID 30661751) for a predicted splice-altering effect.
• REVEL local predictor lookup: score = 0.271 for 19-10489261-C-T (GRCh38) -- below the ClinGen SVI-calibrated REVEL PP3_Supporting threshold of >=0.644 (Pejaver et al., PMID 36413997).

Still missing

• BayesDel score exists (-0.342965) but has no verified published calibration threshold usable by this pipeline; excluded from PP3 assessment.

Sources

Reasoning

PP5 is not met. The exact variant NM_012289.4:c.1639G>A is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion. No ordinary submission, aggregate label, or non-expert assertion was used as a trigger.

Rule

Apply PP5 only when an exact-variant ClinVar expert-panel classification is Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar exact-variant lookup returned no result for NM_012289.4:c.1639G>A; therefore there is no expert-panel Pathogenic or Likely pathogenic classification eligible to support PP5.

Sources

Reasoning

BA1 is not met. The variant frequency is far below the generic benign stand-alone threshold of >1%: gnomAD v2.1 reports AF 2.787e-05 (7/251166 alleles; 0 homozygotes), and gnomAD v4.1 reports AF 2.1694e-05 (35/1613350 alleles; 0 homozygotes). The highest reported ancestry-specific frequency is South Asian AF 7.69079e-05 in gnomAD v4.1, also far below 1%.

Rule

generic_non_vcep_population_threshold: BA1 requires AF > 0.01

Evidence considered

• Generic non-VCEP BA1 threshold applied: allele frequency >1% is required for BA1.
• gnomAD v2.1: AF 2.787e-05, 7/251166 alleles, 0 homozygotes; highest South Asian AF 6.54236e-05.
• gnomAD v4.1: AF 2.1694e-05, 35/1613350 alleles, 0 homozygotes; highest South Asian AF 7.69079e-05.

Sources

Reasoning

BS1 is not met. The observed population frequency is well below the generic non-VCEP threshold of >0.3%: gnomAD v2.1 AF is 2.787e-05 and gnomAD v4.1 AF is 2.1694e-05; the highest ancestry-specific frequency is 7.69079e-05 in South Asian individuals in gnomAD v4.1. No disease-prevalence or penetrance-specific threshold is available in the case evidence to justify a lower or alternative BS1 cutoff.

Rule

generic_non_vcep_population_threshold: BS1 requires AF > 0.003

Evidence considered

• Generic non-VCEP BS1 threshold applied: allele frequency >0.3% is required for BS1.
• gnomAD v2.1: AF 2.787e-05, grpmax FAF 1.687e-05; highest South Asian AF 6.54236e-05.
• gnomAD v4.1: AF 2.1694e-05, grpmax FAF 3.59e-05; highest South Asian AF 7.69079e-05.

Still missing

• No KEAP1-specific disease-prevalence/penetrance-based maximum credible allele frequency threshold was retrieved.

Sources

Reasoning

BP6 is not met. The exact variant NM_012289.4:c.1639G>A is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Benign or Likely benign assertion. No ordinary submission, aggregate label, or non-expert assertion was used as a trigger.

Rule

Apply BP6 only when an exact-variant ClinVar expert-panel classification is Benign or Likely benign; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar exact-variant lookup returned no result for NM_012289.4:c.1639G>A; therefore there is no expert-panel Benign or Likely benign classification eligible to support BP6.

Sources

Reasoning

PS1 requires a different nucleotide change at the same codon producing the identical amino acid change (p.Val547Ile) that has already been established as pathogenic. This variant (NM_012289.4:c.1639G>A) is absent from ClinVar entirely, so no classified comparator variant at this exact amino acid change exists in the available sources. No VCEP/CSPEC is available for KEAP1 (cspec.found=false, gene_vcep_dir=null), so generic ACMG PS1 logic was used but could not be satisfied due to lack of any comparator record.

Evidence considered

• ClinVar search for KEAP1 c.1639G>A returned no_result / found=false, with evidence_sentence 'This variant is absent from ClinVar.' No comparator entry for an alternate nucleotide change yielding p.Val547Ile was located.

Still missing

• No ClinVar record exists for this variant or for any alternate codon change producing p.Val547Ile.
• No KEAP1-specific VCEP/CSPEC available to define PS1 usage rules for this gene.

Sources

Reasoning

No proband-level de novo evidence is available in the case bundle. There is no documented parental testing showing the variant is absent in both biological parents, and no confirmed maternity/paternity or validated trio context is provided. Generic ACMG/AMP criteria are therefore not met or refuted; PS2 remains not assessed.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo occurrence in a patient with the relevant disease and established maternity/paternity; no applicable KEAP1-specific VCEP specification was available.

Evidence considered

• The consolidated case-evidence bundle contains no family history, trio data, parental genotypes, or de novo assertion for NM_012289.4:c.1639G>A (NP_036421.2:p.(Val547Ile)).
• No publication was identified in the case literature packet that reports this exact variant in a de novo proband-parent context.

Still missing

• Documented proband phenotype and confirmed biological parentage
• Validated testing of both biological parents demonstrating presence or absence of NM_012289.4:c.1639G>A
• Testing methodology, coverage, and confirmation details sufficient to establish a true de novo event

Reasoning

No KEAP1-specific ClinGen VCEP specification was found for this case (cspec.found=false, vcep_materials note='no cspec url available'), so generic ACMG/AMP applies. No functional/biochemical assay data (e.g., Nrf2/ARE reporter activity, KEAP1-Nrf2 degradation, Keap1 substrate binding assays) for c.1639G>A (p.Val547Ile) were identified in any consolidated source. literature_pass.json returned zero PMIDs ('No PMIDs found across evidence sources'), fulltext_map.json is empty, and no publications were retrieved to this case's publications directory. OncoKB returned only gene-level context with no variant-specific reviewed functional evidence (not_reviewed=true, is_variant_specific=false). There is no validated assay evidence available to assess PS3.

Evidence considered

• case_summary.json cspec.found=false and vcep_materials.json note='no cspec url available' indicate no KEAP1 ClinGen VCEP specification is available; generic ACMG/AMP framework applies
• literature_pass.json: total_pmids=0, note='No PMIDs found across evidence sources', criteria_index and criterion_screened both empty
• fulltext_map.json is empty ({}), confirming no full-text papers were retrieved for this case
• OncoKB evidence_sentence: 'OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up.' with is_variant_specific=false and not_reviewed=true

Still missing

• No functional assay literature (e.g., Nrf2 pathway reporter, KEAP1 degron/degradation assay, in vitro binding assay) identified for this variant or codon
• No VCEP-specific functional assay calibration available for KEAP1
• literature_pass.json found zero PMIDs; a targeted literature search for KEAP1 p.Val547Ile functional studies was not possible within the provided bundle

Reasoning

No case series, case-control comparison, affected-carrier count, or statistically supported disease enrichment data for NM_012289.4:c.1639G>A were identified. PS4 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires prevalence in affected individuals to be significantly increased compared with appropriate controls; no applicable KEAP1-specific VCEP framework was available.

Evidence considered

• The consolidated evidence bundle reports no literature PMIDs and no case-control or phenotype-enrichment evidence for this exact variant.

Still missing

• Variant-specific affected-case counts and an appropriate disease-matched control comparison are unavailable.

Reasoning

No applicable KEAP1-specific VCEP or CSPEC framework was retrieved, so the generic ACMG/AMP rule applies. PM3 requires the variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual (with strength determined by the number and quality of such observations). The case-evidence bundle contains no affected-proband observations, family segregation data, phase information, or pathogenic variants reported in trans or cis. Therefore PM3 cannot be assessed from this case and is not applied.

Rule

Generic ACMG/AMP PM3: pathogenic or likely pathogenic variant observed in trans with the variant being evaluated in an affected individual; assess strength according to the number and quality of independent observations.

Evidence considered

• The case summary identifies the variant as KEAP1 NM_012289.4:c.1639G>A (NP_036421.2:p.(Val547Ile)) and reports that no KEAP1-specific CSPEC/VCEP framework was found.
• The consolidated case-evidence bundle contains no case-level proband, family, phase, cis/trans, or inheritance observations relevant to PM3.

Still missing

• Affected-proband observations involving NM_012289.4:c.1639G>A are not available.
• No paired pathogenic or likely pathogenic variant and no confirmed trans phase are documented.
• No family testing or inheritance information is available.

Reasoning

PM5 requires a different missense change at the same residue (position 547) previously established as pathogenic/likely pathogenic. The case's automated PM5 comparator harvesting step explicitly declined to run ('pm5_mode: unknown', 'eligible_for_classic_pm5_search: false'), citing inability to confirm classic same-residue PM5 semantics safely, and returned zero candidates (total_candidates_seen=0, same_residue_candidates=0). ClinVar itself is empty for this gene/variant query in this case, so no independent same-residue comparator was found through other case sources either. This criterion cannot be scored from available evidence.

Evidence considered

• pm5_candidates.json recommendation: 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting,' with candidate_summary showing 0 total_candidates_seen and 0 same_residue_candidates, and an explicit instruction that PM5 should not be applied from this artifact alone.
• ClinVar search for KEAP1 c.1639G>A found no records (absent from ClinVar), providing no independent same-residue comparator.

Still missing

• PM5 comparator candidate harvesting was skipped by the pipeline (pm5_candidates.json: found=false, eligible_for_classic_pm5_search=false); a manual ClinVar/literature search for other pathogenic missense substitutions at KEAP1 residue 547 is needed.
• No ClinVar records were retrieved for this variant or gene position in this case bundle to serve as comparators.

Sources

Reasoning

No suspected de novo occurrence without parental confirmation is documented for this variant. Because the case bundle provides neither a proband de novo observation nor an unconfirmed parental-status report, PM6 cannot be applied.

Rule

Generic ACMG/AMP PM6 concerns a suspected de novo occurrence without confirmation of parental status; no applicable KEAP1-specific VCEP specification was available.

Evidence considered

• The consolidated case-evidence bundle contains no proband description, pedigree, parental testing, or suspected de novo report for NM_012289.4:c.1639G>A.
• No exact-variant publication relevant to suspected de novo evidence was present in the literature packet.

Still missing

• A documented affected proband carrying the variant with a suspected de novo origin
• Parental testing or an explicit report that parental status was unavailable or unconfirmed
• Phenotype consistency with the disease under evaluation

Reasoning

No informative affected or unaffected relatives, meioses, pedigree structure, genotype observations, or segregation analysis are provided. Therefore, cosegregation of NM_012289.4:c.1639G>A with disease cannot be evaluated and PP1 is not assessed.

Rule

Generic ACMG/AMP PP1 requires cosegregation with disease in multiple affected family members; no applicable KEAP1-specific VCEP specification was available.

Evidence considered

• The consolidated case-evidence bundle contains no pedigree, family segregation results, relative phenotypes, or meiosis count for NM_012289.4:c.1639G>A.
• No exact-variant publication relevant to cosegregation was identified in the case literature packet.

Still missing

• Pedigree with clinically characterized relatives
• Genotypes for affected and unaffected informative relatives
• Number of informative meioses and segregation analysis
• Disease phenotype definition and assessment of phenotype consistency in each tested relative

Reasoning

PP2 requires (1) that missense variants are a common mechanism of disease for KEAP1 and (2) a low rate of benign missense variation in the gene. No KEAP1-specific VCEP/CSPEC is available to establish PP2 eligibility for this gene (cspec.found=false; final_classification_framework.found=false, framework_mode=generic_acmg_fallback), and no gene-level missense constraint metric (e.g., gnomAD missense Z-score/o:e ratio) was retrieved in this case's source set to evaluate the benign-missense-rate prong. Without both a citable gene-mechanism statement and a constraint metric from a registered case source, PP2 applicability cannot be determined.

Evidence considered

• OncoKB gene-level annotation notes KEAP1 as 'a tumor suppressor and adaptor protein, recurrently mutated in lung cancer,' but provides no missense-specific mechanism statistics or benign-variation-rate data usable for PP2 scoring.

Still missing

• No missense constraint metric (gnomAD missense Z-score / o:e) for KEAP1 was retrieved in this case bundle.
• No KEAP1 VCEP/CSPEC PP2 eligibility statement is available (gene_vcep_dir=null, cspec.found=false).
• OncoKB evidence pertains to somatic cancer context, not germline missense-mechanism prevalence, so it cannot substitute for a gene-level constraint statement.

Sources

Reasoning

No patient phenotype, clinical presentation, or highly specific disease phenotype is provided for the variant. PP4 cannot be assessed.

Rule

Generic ACMG/AMP PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology; no applicable KEAP1-specific VCEP framework was available.

Evidence considered

• The case bundle contains variant and population/database findings but no clinical phenotype description for an affected individual.

Still missing

• A documented patient phenotype and a disease-specific phenotype match are unavailable.

Reasoning

BS2 cannot be established from the available population data. gnomAD v2.1 and v4.1 report zero homozygotes, but BS2 requires observation of the variant in healthy individuals, typically homozygotes for a fully penetrant dominant condition or hemizygotes for an X-linked condition, together with an appropriate disease model and phenotype assessment. No such healthy-carrier phenotype or disease-model evidence is provided.

Rule

generic_acmg_bs2: requires observation in healthy individuals, especially homozygotes for a fully penetrant dominant disorder or hemizygotes for an X-linked disorder

Evidence considered

• gnomAD v2.1 reports 0 homozygotes among 7 observed alleles.
• gnomAD v4.1 reports 0 homozygotes among 35 observed alleles.
• Absence of homozygotes is not itself qualifying BS2 evidence because no healthy-carrier phenotype assessment or applicable inheritance/penetrance model is available.

Still missing

• No curated healthy-carrier cohort with phenotype and genotype data was identified.
• No sufficiently established KEAP1 inheritance, penetrance, and disease-prevalence model was retrieved for applying BS2.

Sources

Reasoning

No KEAP1-specific ClinGen VCEP specification was found for this case, so generic ACMG/AMP applies. No functional/biochemical assay data showing normal/wild-type function for c.1639G>A (p.Val547Ile) were identified in any consolidated source. literature_pass.json returned zero PMIDs, fulltext_map.json is empty, and OncoKB provided only gene-level (not variant-specific) context. There is no validated assay evidence available to assess BS3.

Evidence considered

• case_summary.json cspec.found=false and vcep_materials.json note='no cspec url available' indicate no KEAP1 ClinGen VCEP specification is available; generic ACMG/AMP framework applies
• literature_pass.json: total_pmids=0, note='No PMIDs found across evidence sources'
• fulltext_map.json is empty ({}), confirming no full-text papers were retrieved for this case
• OncoKB evidence_sentence indicates no variant-specific reviewed functional evidence exists (is_variant_specific=false, not_reviewed=true)

Still missing

• No functional assay literature demonstrating normal/wild-type-like activity for this variant identified
• No VCEP-specific functional assay calibration available for KEAP1
• literature_pass.json found zero PMIDs; a targeted literature search for KEAP1 p.Val547Ile functional studies was not possible within the provided bundle

Reasoning

No unaffected relatives carrying or lacking the variant, no clinically informative family members, and no non-segregation analysis are documented. The absence of family data prevents assessment of whether the variant fails to segregate with disease; BS4 is not assessed.

Rule

Generic ACMG/AMP BS4 concerns lack of segregation in affected family members; no applicable KEAP1-specific VCEP specification was available.

Evidence considered

• The consolidated case-evidence bundle contains no family genotype/phenotype data or non-segregation observations for NM_012289.4:c.1639G>A.
• No exact-variant publication relevant to non-segregation evidence was identified in the case literature packet.

Still missing

• Clinically characterized affected and unaffected relatives
• Reliable genotypes for informative relatives
• Assessment of whether the variant is present in unaffected relatives or absent in affected relatives
• Consideration of age-dependent penetrance, phenocopies, and phenotype misclassification before interpreting non-segregation

Reasoning

BP1 applies when missense variants are not a recognized mechanism of disease for a gene (i.e., disease is driven primarily by truncating/LOF variants), and would generally be mutually exclusive with PP2 applicability. No KEAP1-specific VCEP/CSPEC or missense-constraint data confirming or excluding a missense disease mechanism was available in this case's registered sources (no cspec, no gene-level missense mechanism statement from a citable source), so BP1 cannot be reliably scored either met or not_met from the available evidence.

Evidence considered

• No registered case source (ClinVar, OncoKB, gnomAD, or a KEAP1 VCEP/CSPEC) provided a gene-level missense-mechanism statement or missense constraint metric sufficient to assess BP1 in either direction.

Still missing

• No VCEP/CSPEC or constraint-metric source establishing whether missense variation is or is not a recognized KEAP1 disease mechanism was available in this case bundle.
• Determination requires the same missing gene-mechanism/constraint data noted under PP2.

Reasoning

No applicable KEAP1-specific VCEP or CSPEC framework was retrieved, so the generic ACMG/AMP rule applies. BP2 requires the variant to be observed in trans with a pathogenic variant for a recessive disorder, or in cis with a pathogenic variant in a dominant disorder. The case-evidence bundle provides no phase-resolved genotype, affected-proband observation, paired pathogenic variant, or inheritance-mode evidence. Therefore BP2 cannot be assessed from this case and is not applied.

Rule

Generic ACMG/AMP BP2: variant observed in trans with a pathogenic variant for a recessive disorder, or in cis with a pathogenic variant for a dominant disorder; phase and inheritance mode must be established.

Evidence considered

• The case summary identifies KEAP1 NM_012289.4:c.1639G>A and reports no retrieved KEAP1-specific CSPEC/VCEP framework.
• The consolidated case-evidence bundle contains no case-level phase, cis/trans, paired-variant, proband, or inheritance observations relevant to BP2.

Still missing

• No pathogenic or likely pathogenic paired variant is documented.
• No confirmed cis or trans phase is available.
• The relevant inheritance mode and family segregation are not established for this case.

Reasoning

No patient-level phenotype or molecular finding demonstrates that the relevant disease is explained by an alternative genetic cause. BP5 cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP BP5 requires evidence that an alternate molecular basis explains the phenotype; no applicable KEAP1-specific VCEP framework was available.

Evidence considered

• The consolidated bundle contains no clinical case description, segregation data, or alternative pathogenic molecular diagnosis for this case.

Still missing

• An affected individual with a confirmed alternative molecular explanation for the phenotype is unavailable.