--- name: rare-disease-cancer description: | Plan rare disease, hereditary disease, cancer risk, carrier-relevance, and observed-condition source investigation from public targets or selected active genome evidence. tools: - phenotype.plan_risk_investigation - phenotype.normalize_terms - phenotype.retrieve_gene_disease_associations - phenotype.compare_disease_evidence - phenotype.compare_gene_hpo_evidence - research.list_sources - variant.gather_gene_context - variant.gather_allele_context - gnomad.fetch_population_frequency - research.record - research.query - active_genome_index.classify_genotype_support - active_genome_index.classify_region_callability mutating: true --- # Condition Review Use this skill when the user asks about rare disease, hereditary disease, cancer risk genes, hereditary cancer, GeneCards-style gene context, MalaCards disease context, HPO/phenotype-to-disease review, HPO-style phenotype-to-gene review, carrier-relevance evidence, observed-condition review, or disease-gene source review. **Not for common-trait phenotypes.** Common, complex-disease, GWAS-style, or drug-target candidate-gene questions use the matching source-specific tool. Use this skill when the phenotype is explicitly rare/Mendelian, HPO-style, or hereditary cancer. ## Contract Support both public-only questions and selected active genome evidence. - Public-only questions stay public-only. - Active genome evidence is used only when the current chat has selected or approved active genome access. - GeneCards and MalaCards are context sources, not clinical-validity sources by themselves. - Cancer-gene role, somatic cancer evidence, and inherited germline risk remain separate unless a reviewed source links them. - Carrier-review output consumes ClinVar `carrier_relevance` groups and ranks review targets by evidence strength plus missing interpretation gates. - Observed-condition review consumes observed-condition, uncertainty/conflict, risk-association, benign/counterevidence, and population-context groups. - Reviewed source findings are stored before final interpretation or reporting. - HPO and symptom overlap can prioritize review targets, but it is not a diagnosis. ## First Tool Call `phenotype.plan_risk_investigation` first. Provide any public targets the user gave: - `phenotype.plan_risk_investigation` with `{"question":"BRCA1 hereditary breast cancer risk","gene":"BRCA1","investigation_type":"cancer_risk"}` - `phenotype.plan_risk_investigation` with `{"question":"carrier relevance review","investigation_type":"carrier_review"}` - `phenotype.plan_risk_investigation` with `{"question":"observed ClinVar condition review","investigation_type":"observed_condition_review"}` For a selected Active Genome Index, add: - `phenotype.plan_risk_investigation` with `{"question":"rare disease review for GENE2","gene":"GENE2","include_active_genome_index":true}` If the user did not select active genome evidence, do not add active genome parameters. For phenotype-first questions, normalize and rank the public targets: - `phenotype.normalize_terms` with `{"text":"ataxia; microcephaly; seizures; HP:0001250"}` - `phenotype.retrieve_gene_disease_associations` with `{"genes":["PIEZO2"]}` - `phenotype.compare_disease_evidence` with `{"phenotypes":["ataxia","microcephaly","seizures"],"candidate_diseases":["condition A","condition B"],"source_records":[{"diseases":["condition A"],"verified_fields":{"diseases":["condition A"],"phenotypes":["ataxia"]},"support_spans":[{"field":"phenotypes","text":"source-backed ataxia text"}]}]}` - `phenotype.compare_disease_evidence` with `{"hpo_ids":["HP:0000822","HP:0001965"],"genes":["PIEZO2"]}` - `phenotype.compare_gene_hpo_evidence` with `{"phenotypes":["ataxia","microcephaly"],"genes":["PNKP","SPG7"],"source_records":[{"genes":["PNKP"],"verified_fields":{"genes":["PNKP"],"phenotypes":["ataxia","microcephaly"]},"support_spans":[{"field":"genes","text":"source-backed PNKP text"}]}]}` Use `phenotype.compare_disease_evidence` when the answer choices are diseases or syndromes. Also use it when the input is HPO terms plus known or candidate genes but the requested output is a disease name, syndrome name, or OMIM-style diagnosis. In that shape, gene resolution is not the answer; the load-bearing step is within-gene disease-family discrimination by the patient's specific HPO pattern. `phenotype.retrieve_gene_disease_associations` returns the GenCC primary gene-disease association set for supplied genes. `phenotype.compare_disease_evidence` uses that association set as the gene-derived candidate universe and uses HPO disease annotations only for phenotype terms. Use `phenotype.compare_gene_hpo_evidence` for HPO IDs, patient-specific phenotypes, rare-disease phenotype matching, or single-subject causal-gene questions. Keep this phenotype/HPO evidence separate from population-trait, drug-target, and perturbation evidence. When HPO IDs are available, pass them so public phenotype-to-gene annotation can be checked across the full candidate set. Do not pick a gene from partially reviewed evidence; gather better source support or state that the source evidence is incomplete. ## Source Review Use the investigation guidance to decide which source to review next: - ClinVar for exact variant assertions and review status. - gnomAD for public population frequency when an exact allele matters. - ClinGen and GenCC for gene-disease validity. - GeneReviews for inheritance, mechanism, penetrance, and disease context. - GeneCards for gene aliases, function, pathways, and disease-association triage. - MalaCards for disease aliases, phenotype context, and associated genes. - NCI cancer genetics for hereditary cancer background and counseling boundaries. - COSMIC Cancer Gene Census for cancer-gene role context, not standalone germline-risk evidence. - HPO for phenotype identifiers and synonyms. - MONDO for disease identifiers, aliases, and ontology context. - Orphanet and OMIM for rare disease phenotype and gene relationship context. ## Evidence Checks For active genome evidence: - Use `variant.gather_gene_context` for selected genes. - Use `variant.gather_allele_context` for selected exact alleles. - Use `active_genome_index.classify_genotype_support` before personal wording about an observed allele. - Use `active_genome_index.classify_region_callability` before negative or absence wording. - Use `gnomad.fetch_population_frequency` when public frequency is missing and would change interpretation. For phenotype-first ranking, use reviewed records with source-backed fields or support spans. Direct answers require a source to support both the candidate and the relevant phenotype, disease, or HPO context. ## Answering Mention Active Genome Index use only when it changes the result, limitation, or next action. Keep risk language qualitative unless a cited source gives a quantitative estimate. Recommend clinical genetics confirmation for medical decisions. ## Cross-Capability Synthesis A scope-limited result from this capability is not a final user-facing answer when other Genomi capabilities can contribute orthogonal evidence to the same question. Returning "cannot answer" while applicable capabilities remain unexamined is a host-agent failure mode. ## Tools ### phenotype.compare_disease_evidence Compare supplied or primary gene-derived diseases against phenotype/HPO evidence without selecting the diagnosis. **Use when**: Compares phenotype/HPO terms against supplied diseases, disease source records, or primary gene-disease associations. Uses GenCC primary gene-disease associations as the gene-derived disease candidate universe when gene symbols are supplied. **Why necessary**: Candidate diseases must be compared against phenotype/HPO evidence without letting the tool choose a diagnosis. **Result semantics**: Returns phenotype/disease evidence rows, disease identifiers, HPO overlap counts, and source coverage; the host agent chooses the answer. The tool uses primary gene-disease retrieval for enumeration and HPO disease annotations for phenotype terms. ### phenotype.compare_gene_hpo_evidence Compare candidate genes using phenotype, HPO, and curated rare-disease annotation evidence only. **Use when**: Returns phenotype, HPO, OMIM, Orphanet, and rare-disease annotation evidence for candidate genes. **Why necessary**: Rare-disease candidate genes need HPO/phenotype evidence, not GWAS, drug-target, or pathway priors. **Not for**: common-trait GWAS ranking, drug-target evidence, or medication response. **Example prompts**: Which of these genes best matches ataxia and microcephaly? **Result semantics**: Returns source-local phenotype/HPO evidence only; the host agent decides whether this prior matches the question. ### phenotype.normalize_terms Normalize phenotype text and HPO IDs into public evidence-review targets. **Use when**: Normalizes supplied HPO IDs or free-text phenotypes into public evidence-review targets. **Why necessary**: Free-text symptoms need normalization before HPO and rare-disease tools can compare them reliably. **Result semantics**: Returns lexical phenotype normalization and safe public targets; it does not diagnose or call external ontology APIs. ### phenotype.plan_risk_investigation Plan rare disease, cancer risk, carrier-relevance, or observed-condition investigation from public targets and optionally selected Active Genome Index evidence. **Use when**: Returns rare disease, hereditary disease, hereditary cancer, cancer-risk-gene, carrier-relevance, observed-condition, and disease-gene source-review plans. Can include selected active-genome-index review targets when explicitly supplied or approved. **Why necessary**: Broad disease and cancer-risk questions need declared source-review boundaries before any personal-risk wording. **Example prompts**: Any inherited disease or cancer-risk findings worth following up? **Result semantics**: Returns structured investigation guidance, relevant public source classes, reviewed-research gaps, and optional selected active-genome-index `candidate_review_groups`. Without include_active_genome_index or explicit matches, the operation stays public-only. GeneCards and MalaCards are treated as context sources that require cross-checking before clinical, carrier, or personal-risk wording. ### phenotype.retrieve_gene_disease_associations Retrieve primary gene-disease associations from GenCC for supplied gene symbols. **Use when**: Returns GenCC primary gene-disease associations for supplied genes, filtered to declared validity classifications. **Why necessary**: Gene-disease validity should come from primary association sources before phenotype matching or diagnosis-like wording. **Result semantics**: Returns a primary gene-disease candidate universe for downstream phenotype/HPO comparison. Does not ingest agent-supplied source records and does not diagnose.