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

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

▶ list_studies
{
 "search": "TCGA breast pan can atlas"
}

◀ 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 … (35166 more chars)

◀ result
{"result":[{"cancer_study_identifier":"brca_tcga_pan_can_atlas_2018","name":"Breast Invasive Carcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"brca","sample_count":1084,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=brca_tcga_pan_can_atlas_2018"}]}

▶ 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"
}

◀ 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":"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":"Y220C","mutation_type":"Missense_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":"X225_splice","mutation_type":"Splice_Site","altered_samples":5,"profiled_samples":1066,"frequency_pct":0.5,"total_mutation_events":5},{"mutation_variant":"I195T","mutation_type":"Missense_Mutation","altered_samples":5,"profiled_samples":1066,"frequency_pct":0.5,"total_mutation_events":5}]}

═ answer (success)
In the **[Breast Invasive Carcinoma (TCGA, PanCancer Atlas)](https://www.cbioportal.org/study/summary?id=brca_tcga_pan_can_atlas_2018)** study (1,066 samples profiled for TP53 mutations), the most frequent specific TP53 mutation is:

**R175H** (missense mutation) — 21 samples, 2.0% of TP53-profiled samples.

This is followed by R273H (13 samples, 1.2%) and several recurrent nonsense/splice-site and missense variants (R196*, R342*, R213*, Y220C, etc.) each in 5–8 samples. Note that TP53 overall is mutated in a much larger fraction of this cohort (~30–35%), but no single amino-acid change dominates — mutations are spread across many distinct missense and truncating variants, consistent with TP53's broad mutational spectrum in cancer.

You can explore the full variant breakdown directly:

[View TP53 mutations in Breast Invasive Carcinoma (TCGA, PanCancer Atlas)](https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pan_can_atlas_2018&Z_SCORE_THRESHOLD=2.0&RPPA_SCORE_THRESHOLD=2.0&profileFilter=mutations%2Cgistic&case_set_id=brca_tcga_pan_can_atlas_2018_all&gene_list=TP53&geneset_list=%20&tab_index=tab_visualize&Action=Submit)