Q (sonnet): show me all KRAS mutations in colorectal cancer that are not at position 12

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

◀ result
{"success":true,"message":"Found 3 matching studies. Pick the best match (prefer TCGA → prefer PanCancer Atlas), use its metadata to call the appropriate navigation tool(s) and generate URLs immediately. Present other studies as alternatives.","data":{"totalCount":3,"studiesWithMetadata":[{"studyId":"coadread_tcga","name":"Colorectal Adenocarcinoma (TCGA, Firehose Legacy)","sampleCount":640,"studyViewUrl":"https://www.cbioportal.org/study?id=coadread_tcga","metadata":{"clinicalAttributeIds":["AGE","AJCC_METASTASIS_PATHOLOGIC_PM","AJCC_NODES_PATHOLOGIC_PN","AJCC_PATHOLOGIC_TUMOR_STAGE","AJCC_STAGING_EDITION","AJCC_TUMOR_PATHOLOGIC_PT","BRAF_GENE_ANALYSIS_INDICATOR","BRAF_GENE_ANALYSIS_RESULT","CANCER_TYPE","CANCER_TYPE_DETAILED","CLINICAL_STAGE","CLIN_M_STAGE","CLIN_N_STAGE","CLIN_T_STAGE","DAYS_TO_COLLECTION","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS","DAYS_TO_PATIENT_PROGRESSION_FREE","DAYS_TO_SPECIMEN_COLLECTION","DAYS_TO_TUMOR_PROGRESSION","DFS_MONTHS","DFS_STATUS","DISEASE_CODE","ETHNICITY","EXTRANODAL_INVOLVEMENT","FORM_COMPLETION_DATE","FRACTION_GENOME_ALTERED","HEIGHT","HISTOLOGICAL_DIAGNOSIS","HISTORY_NEOADJUVANT_TRTYN","HISTORY_OTHER_MALIGNANCY","ICD_10","ICD_O_3_HISTOLOGY","ICD_O_3_SITE","INFORMED_CONSENT_VERIFIED","INITIAL_PATHOLOGIC_DIAGNOSIS_METHOD","INITIAL_PATHOLOGIC_DX_YEAR","IS_FFPE","KRAS_GENE_ANALYSIS_INDICATOR","KRAS_MUTATION","LONGEST_DIMENSION","LYMPHOVASCULAR_INVASION_INDICATOR","LYMPH_NODES_EXAMINED","LYMPH_NODES_EXAMINED_HE_COUNT","LYMPH_NODES_EXAMINED_IHC_COUNT","LYMPH_NODE_EXAMINED_COUNT","METHOD_OF_SAMPLE_PROCUREMENT","MUTATION_COUNT","NEW_TUMOR_EVENT_AFTER_INITIAL_TREATMENT","OCT_EMBEDDED","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_METHOD_OF_SAMPLE_PROCUREMENT","OTHER_PATIENT_ID","OTHER_SAMPLE_ID","PATHOLOGY_REPORT_FILE_NAME","PATHOLOGY_REPORT_UUID","PERINEURAL_INVASION","PHARMACEUTICAL_TX_ADJUVANT","PRIMARY_SITE_PATIENT","PROJECT_CODE","PROSPECTIVE_COLLECTION","RACE","RADIATION_TREATMENT_ADJUVANT","RESIDUAL_TUMOR","RETROSPECTIVE_COLLECTION","SAMPLE_COUNT","SAMPLE_INITIAL_WEIGHT","SAMPLE_TYPE","SAMPLE_TYPE_ID","SEX","SHORTEST_DIMENSION","SITE_OF_TUMOR_TISSUE","SOMATIC_STATUS","SPECIMEN_CURRENT_WEIGHT","SPECIMEN_FREEZING_METHOD","SPECIMEN_SECOND_LONGEST_DIMENSION","STAGE_OTHER","TIME_BETWEEN_CLAMPING_AND_FREEZING","TIME_BETWEEN_EXCISION_AND_FREEZING","TISSUE_SOURCE_SITE","TMB_NONSYNONYMOUS","TREATMENT_OUTCOME_FIRST_COURSE","TUMOR_STATUS","VASCULAR_INVASION_INDICATOR","VIAL_NUMBER","WEIGHT"],"molecularProfileIds":["coadread_tcga_gistic","coadread_tcga_linear_CNA","coadread_tcga_methylation_hm450","coadread_tcga_mrna","coadread_tcga_mrna_median_Zscores","coadread_tcga_mrna_median_all_sample_Zscores","coadread_tcga_mutations","coadread_tcga_protein_quantification","coadread_tcga_protein_quantification_zscores","coadread_tcga_rna_seq_v2_mrna","coadread_tcga_rna_seq_v2_mrna_median_Zscores","coadread_tcga_rna_seq_v2_mrna_median_all_sample_Zscores","coadread_tcga_rppa","coadread_tcga_rppa_Zscores"],"heatmapProfileIds":["coadr … (4966 more chars)

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

▶ clickhouse_list_table_columns
{
 "table": "gene_mutation_variants_in_study"
}

◀ 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
{"columns":[]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT mutation_variant, mutation_type, altered_samples, profiled_samples, frequency_pct, total_mutation_events
FROM gene_mutation_variants_in_study(study = 'coadread_tcga_pan_can_atlas_2018', gene = 'KRAS')
WHERE NOT startsWith(mutation_variant, 'G12')
ORDER BY altered_samples DESC
",
 "max_rows": 200
}

◀ result
{"rows":[{"mutation_variant":"G13D","mutation_type":"Missense_Mutation","altered_samples":37,"profiled_samples":534,"frequency_pct":6.9,"total_mutation_events":37},{"mutation_variant":"A146T","mutation_type":"Missense_Mutation","altered_samples":16,"profiled_samples":534,"frequency_pct":3,"total_mutation_events":16},{"mutation_variant":"Q61H","mutation_type":"Missense_Mutation","altered_samples":4,"profiled_samples":534,"frequency_pct":0.7,"total_mutation_events":4},{"mutation_variant":"K117N","mutation_type":"Missense_Mutation","altered_samples":4,"profiled_samples":534,"frequency_pct":0.7,"total_mutation_events":4},{"mutation_variant":"Q61K","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":534,"frequency_pct":0.6,"total_mutation_events":3},{"mutation_variant":"G13C","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":534,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"Q61R","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":534,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L19F","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Q61L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Y71C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"E98*","mutation_type":"Nonsense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A11_G12dup","mutation_type":"In_Frame_Ins","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A146V","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Q61E","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Q61P","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"P34L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A59T","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"R68S","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Q22K","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A155D","mutation_type":"Missense_Mutation","altered_sampl … (77 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "KRAS: MUT != (12-12*)"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS%3A+MUT+%21%3D+%2812-12*%29&case_set_id=coadread_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS%3A+MUT+%21%3D+%2812-12*%29&case_set_id=coadread_tcga_pan_can_atlas_2018_all","data":{"studyIds":["coadread_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":594}],"genes":["KRAS"],"caseSetId":"coadread_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

═ answer (success)
[View KRAS mutations excluding codon 12 — Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)](https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS%3A+MUT+%21%3D+%2812-12*%29&case_set_id=coadread_tcga_pan_can_atlas_2018_all)

Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for KRAS, restricted to non-codon-12 events, in the 594-sample TCGA PanCancer Atlas colorectal cohort.

**Other colorectal cohorts available**, if you'd like these numbers for a different dataset instead:
- [Colorectal Adenocarcinoma (TCGA, Firehose Legacy)](https://www.cbioportal.org/study?id=coadread_tcga) — 640 samples
- [Colorectal Adenocarcinoma (TCGA, Nature 2012)](https://www.cbioportal.org/study?id=coadread_tcga_pub) — 276 samples