Q (haiku): What are the most frequent EGFR mutation variants in lung adenocarcinoma and what percentage are known hotspot mutations?

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

▶ search_oncotree
{
 "search_term": "lung adenocarcinoma"
}

◀ 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":[{"code":"LUAD","name":"Lung Adenocarcinoma","score":80,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUAD"},{"code":"LAIS","name":"Lung Adenocarcinoma In Situ","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LAIS"}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT *
FROM gene_mutation_variants_in_study(study = 'luad_tcga_pan_can_atlas_2018', gene = 'EGFR')
ORDER BY frequency_pct DESC;
"
}

◀ result
{"rows":[{"mutation_variant":"L858R","mutation_type":"Missense_Mutation","altered_samples":23,"profiled_samples":566,"frequency_pct":4.1,"total_mutation_events":23},{"mutation_variant":"E746_A750del","mutation_type":"In_Frame_Del","altered_samples":16,"profiled_samples":566,"frequency_pct":2.8,"total_mutation_events":16},{"mutation_variant":"E709_T710delinsD","mutation_type":"In_Frame_Del","altered_samples":3,"profiled_samples":566,"frequency_pct":0.5,"total_mutation_events":3},{"mutation_variant":"L861Q","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":566,"frequency_pct":0.5,"total_mutation_events":3},{"mutation_variant":"L747_A750delinsP","mutation_type":"In_Frame_Del","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L62R","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"T790M","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L747_T751del","mutation_type":"In_Frame_Del","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"G719A","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"S768I","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"H773dup","mutation_type":"In_Frame_Ins","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"K754I","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"K754_I759del","mutation_type":"In_Frame_Del","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"E545Q","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"X210_splice","mutation_type":"Splice_Region","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"R1052I","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A767_V769dup","mutation_type":"In_Frame_Ins","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"G901V","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"V300M","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"K754E","mutation_type … (3054 more chars)

▶ resolve_and_route
{
 "studyIds": [
  "luad_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":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566,"studyViewUrl":"https://www.cbioportal.org/study?id=luad_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":["luad_tcga_pan_can_atlas_2018_gistic","luad_tcga_pan_can_atlas_2018_log2CNA","luad_tcga_pan_can_atlas_2018_mutations","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa","luad_tcga_pan_can_atlas_2018_rppa_Zscores","luad_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["luad_tcga_pan_can_atlas_2018_armlevel_cna","luad_tcga_pan_can_atlas_2018_genetic_ancestry","luad_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","luad_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","generic_assay_armlevel_cna","generic_assay_genetic_ancestry","generic_assay_methylation"]}}]}}

▶ navigate_to_results_view
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "EGFR"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=EGFR&case_set_id=luad_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=EGFR&case_set_id=luad_tcga_pan_can_atlas_2018_all","data":{"studyIds":["luad_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566}],"genes":["EGFR"],"caseSetId":"luad_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

═ answer (success)
## EGFR Mutations in Lung Adenocarcinoma (TCGA)

**Study:** Lung Adenocarcinoma (TCGA, PanCancer Atlas)  
**Samples profiled:** 566

### Most Frequent EGFR Variants

| Variant | Type | # Samples | Frequency |
|---------|------|-----------|-----------|
| **L858R** | Missense | 23 | **4.1%** |
| **E746_A750del** | In-frame deletion | 16 | **2.8%** |
| E709_T710delinsD | In-frame deletion | 3 | 0.5% |
| L861Q | Missense | 3 | 0.5% |
| Remaining (31 variants) | Mixed | 21 | 3.7% |

### Hotspot Mutations

**Known EGFR hotspots represent ~7.4% of profiled samples:**

- **L858R** (4.1%): Tyrosine kinase domain point mutation — canonical hotspot associated with TKI sensitivity
- **Exon 19 deletions** (E746_A750del + E709_T710delinsD + related deletions = 3.8%): Exon 19 in-frame deletions are canonical sensitizing hotspots (predominantly E746_A750del at 2.8%)
- **L861Q** (0.5%): Exon 21 point mutation associated with TKI sensitivity

**Subtotal hotspots:** 23 + 16 + 3 + 3 = **45 samples / 566 = 7.9%**

The top two variants (L858R + E746_A750del) alone account for **6.9%** of all profiled samples. These represent the two most common sensitizing mutations to EGFR tyrosine kinase inhibitors in LUAD. The remaining variants are rare (≤0.5% each), with G719A/C, T790M, and other exon 18/20 mutations each observed in ≤0.4% of cases.

---

**[View interactive mutation details and lollipop plot](https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=EGFR&case_set_id=luad_tcga_pan_can_atlas_2018_all)** — Mutations Tab with variant frequencies and structural visualization.