Q (haiku): What is the most frequent mutation in the TP53 gene in the TCGA breast cancer study?

▶ read_guide
{
 "uri": "cbioportal://mutation-frequency-guide"
}

▶ resolve_and_route
{
 "studyKeywords": [
  "TCGA",
  "breast"
 ]
}

◀ result
# Mutation Frequency Analysis Guide

## IMPORTANT: Reporting Mutation Frequencies
- **ALWAYS report frequencies as percentages**, not raw counts: `frequency = (altered_samples / total_profiled_samples) × 100`
- For quick frequency lookups, **prefer the TCGA Pan-Cancer Atlas study first**, then offer to expand to other studies
- When reporting across multiple studies, show **ranges** (e.g., "TP53 is mutated in 30–60% of samples") rather than a single average
- **NEVER** sum mutation events across studies to compute an aggregate frequency — this can exceed 100% due to double-counting
- Warn users that samples may overlap across cohorts (e.g., MSK studies may share patients)
- **Choose and state the counting unit**: use patient-level frequencies for prevalence/rate questions unless the user explicitly asks for samples; use sample-level frequencies when the user asks about samples.
- **For "across cancer types" questions**, jump to the [Cross-Cancer-Type Mutation Frequency](#cross-cancer-type-mutation-frequency) section below — there is one correct recipe and several common wrong ones.

## Counting Unit: Samples vs Patients

Before answering any mutation count or frequency question, decide whether the unit is samples or patients and state that choice in the answer.

| User wording | Counting unit |
|--------------|---------------|
| "prevalence", "rate", "fraction of patients", "patients with", "how common is" | Patient-level: `COUNT(DISTINCT patient_unique_id)` |
| "samples", "specimens", "biopsies", sample-level cohort composition | Sample-level: `COUNT(DISTINCT sample_unique_id)` |
| Ambiguous | Ask, or default to patient-level for prevalence/rate language and say so |

### Cross-study sample-count caveat

When an answer touches more than one study and reports a sample count, prepend a one-line caveat:

> Sample IDs are unique within cBioPortal study prefixes, not guaranteed biological-sample identifiers across studies; overlapping cohorts can count the same patient/sample more than once.

Prefer one of these safer approaches:

- Use a shipped `cancer_study_query_preferences` cohort such as `pan_cancer_tcga` or `all_studies_non_redundant`.
- Restrict to one named study.
- Aggregate by `patient_unique_id` when the biological question is patient prevalence.

## STOP rule: a frequency above 100% means your query is wrong

If your query returns a frequency over 100%, **do not try to debug or explain the data inconsistency to the user**. The cause is always one of these query bugs:

- Summing mutation events instead of `COUNT(DISTINCT sample_unique_id)` for the numerator
- Using a study-wide sample count as the denominator instead of the gene-specific profiled count
- Cross-study aggregation where the same biological sample appears under multiple `sample_unique_id` values (e.g., MSK-IMPACT and MSK-CHORD share patients)
- **Joining the profiled CTE through `gene_panel` / `gene_panel_list` without a WES branch.** `gene_panel_id = 'WES'` is *not* a row in … (36467 more chars)

◀ result
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▶ resolve_and_route
{
 "studyIds": [
  "brca_tcga_pan_can_atlas_2018"
 ]
}

◀ result
{"success":true,"message":"Found 1 study. Use the metadata to call the appropriate navigation tool(s).","data":{"totalCount":1,"studiesWithMetadata":[{"studyId":"brca_tcga_pan_can_atlas_2018","name":"Breast Invasive Carcinoma (TCGA, PanCancer Atlas)","sampleCount":1084,"studyViewUrl":"https://www.cbioportal.org/study?id=brca_tcga_pan_can_atlas_2018","metadata":{"clinicalAttributeIds":["AGE","AJCC_PATHOLOGIC_TUMOR_STAGE","AJCC_STAGING_EDITION","ANEUPLOIDY_SCORE","BUFFA_HYPOXIA_SCORE","CANCER_TYPE","CANCER_TYPE_ACRONYM","CANCER_TYPE_DETAILED","DAYS_LAST_FOLLOWUP","DAYS_TO_BIRTH","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS","DFS_MONTHS","DFS_STATUS","DSS_MONTHS","DSS_STATUS","ETHNICITY","FORM_COMPLETION_DATE","FRACTION_GENOME_ALTERED","GENETIC_ANCESTRY_LABEL","GRADE","HISTORY_NEOADJUVANT_TRTYN","ICD_10","ICD_O_3_HISTOLOGY","ICD_O_3_SITE","INFORMED_CONSENT_VERIFIED","IN_PANCANPATHWAYS_FREEZE","MSI_SCORE_MANTIS","MSI_SENSOR_SCORE","MUTATION_COUNT","NEW_TUMOR_EVENT_AFTER_INITIAL_TREATMENT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_PATIENT_ID","PATH_M_STAGE","PATH_N_STAGE","PATH_T_STAGE","PERSON_NEOPLASM_CANCER_STATUS","PFS_MONTHS","PFS_STATUS","PRIMARY_LYMPH_NODE_PRESENTATION_ASSESSMENT","PRIOR_DX","RACE","RADIATION_THERAPY","RAGNUM_HYPOXIA_SCORE","SAMPLE_COUNT","SAMPLE_TYPE","SEX","SOMATIC_STATUS","SUBTYPE","TBL_SCORE","TISSUE_PROSPECTIVE_COLLECTION_INDICATOR","TISSUE_RETROSPECTIVE_COLLECTION_INDICATOR","TISSUE_SOURCE_SITE","TISSUE_SOURCE_SITE_CODE","TMB_NONSYNONYMOUS","TUMOR_TISSUE_SITE","TUMOR_TYPE","WEIGHT","WINTER_HYPOXIA_SCORE"],"molecularProfileIds":["brca_tcga_pan_can_atlas_2018_gistic","brca_tcga_pan_can_atlas_2018_log2CNA","brca_tcga_pan_can_atlas_2018_mutations","brca_tcga_pan_can_atlas_2018_protein_quantification","brca_tcga_pan_can_atlas_2018_protein_quantification_zscores","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","brca_tcga_pan_can_atlas_2018_rppa","brca_tcga_pan_can_atlas_2018_rppa_Zscores","brca_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["brca_tcga_pan_can_atlas_2018_armlevel_cna","brca_tcga_pan_can_atlas_2018_genetic_ancestry","brca_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","brca_tcga_pan_can_atlas_2018_methylation_hm450","brca_tcga_pan_can_atlas_2018_phosphoprotein_quantification"],"heatmapProfileIds":["brca_tcga_pan_can_atlas_2018_protein_quantification_zscores","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","brca_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","brca_tcga_pan_can_atlas_2018_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","generic_assay_armlevel_cna","generic_assay_genetic_anc … (83 more chars)

▶ clickhouse_run_select_query
{
 "query": "
SELECT *
FROM gene_mutation_variants_in_study(study = 'brca_tcga_pan_can_atlas_2018', gene = 'TP53')
ORDER BY altered_samples DESC
LIMIT 10
",
 "max_rows": 20
}

◀ result
{"rows":[{"mutation_variant":"R175H","mutation_type":"Missense_Mutation","altered_samples":21,"profiled_samples":1066,"frequency_pct":2,"total_mutation_events":21},{"mutation_variant":"R273H","mutation_type":"Missense_Mutation","altered_samples":13,"profiled_samples":1066,"frequency_pct":1.2,"total_mutation_events":13},{"mutation_variant":"R196*","mutation_type":"Nonsense_Mutation","altered_samples":8,"profiled_samples":1066,"frequency_pct":0.8,"total_mutation_events":8},{"mutation_variant":"Y220C","mutation_type":"Missense_Mutation","altered_samples":7,"profiled_samples":1066,"frequency_pct":0.7,"total_mutation_events":7},{"mutation_variant":"R342*","mutation_type":"Nonsense_Mutation","altered_samples":7,"profiled_samples":1066,"frequency_pct":0.7,"total_mutation_events":7},{"mutation_variant":"R213*","mutation_type":"Nonsense_Mutation","altered_samples":7,"profiled_samples":1066,"frequency_pct":0.7,"total_mutation_events":7},{"mutation_variant":"H193R","mutation_type":"Missense_Mutation","altered_samples":6,"profiled_samples":1066,"frequency_pct":0.6,"total_mutation_events":6},{"mutation_variant":"H179R","mutation_type":"Missense_Mutation","altered_samples":6,"profiled_samples":1066,"frequency_pct":0.6,"total_mutation_events":6},{"mutation_variant":"I195T","mutation_type":"Missense_Mutation","altered_samples":5,"profiled_samples":1066,"frequency_pct":0.5,"total_mutation_events":5},{"mutation_variant":"R248W","mutation_type":"Missense_Mutation","altered_samples":5,"profiled_samples":1066,"frequency_pct":0.5,"total_mutation_events":5}]}

▶ navigate_to_results_view
{
 "studyIds": [
  "brca_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "TP53"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pan_can_atlas_2018&gene_list=TP53&case_set_id=brca_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pan_can_atlas_2018&gene_list=TP53&case_set_id=brca_tcga_pan_can_atlas_2018_all","data":{"studyIds":["brca_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"brca_tcga_pan_can_atlas_2018","name":"Breast Invasive Carcinoma (TCGA, PanCancer Atlas)","sampleCount":1084}],"genes":["TP53"],"caseSetId":"brca_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

═ answer (success)
## Most Frequent TP53 Mutation in TCGA Breast Cancer

The most frequent TP53 mutation in the **Breast Invasive Carcinoma (TCGA, PanCancer Atlas)** study is **R175H**, a missense mutation found in **21 samples out of 1,066 profiled** (2.0% frequency).

### Top 10 TP53 Variants:

| Mutation | Type | Samples | Frequency |
|----------|------|---------|-----------|
| **R175H** | Missense | 21 / 1,066 | **2.0%** |
| R273H | Missense | 13 / 1,066 | 1.2% |
| R196* | Nonsense | 8 / 1,066 | 0.8% |
| Y220C | Missense | 7 / 1,066 | 0.7% |
| R342* | Nonsense | 7 / 1,066 | 0.7% |
| R213* | Nonsense | 7 / 1,066 | 0.7% |
| H193R | Missense | 6 / 1,066 | 0.6% |
| H179R | Missense | 6 / 1,066 | 0.6% |
| I195T | Missense | 5 / 1,066 | 0.5% |
| R248W | Missense | 5 / 1,066 | 0.5% |

**R175H** is a well-known hotspot mutation in TP53 that disrupts DNA binding. The mutations show a mix of missense variants (which may preserve some function) and nonsense/truncating mutations.

[View TP53 mutations in detail](https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pan_can_atlas_2018&gene_list=TP53&case_set_id=brca_tcga_pan_can_atlas_2018_all) — includes a lollipop plot showing the position and frequency of all variants.