Rare Disease Cancer

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.