Q (sonnet-5.5): tell me about IDH1 mutations in glioma

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

◀ 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)

▶ list_studies
{
 "search": "glioma",
 "limit": 50
}

◀ result
{"result":[{"cancer_study_identifier":"glioma_mskcc_2019","name":"Glioma (MSK, Clin Cancer Res 2019)","type_of_cancer_id":"difg","sample_count":1004,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=glioma_mskcc_2019"},{"cancer_study_identifier":"difg_glass","name":"Diffuse Glioma (GLASS Consortium)","type_of_cancer_id":"difg","sample_count":693,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=difg_glass"},{"cancer_study_identifier":"difg_tcga_gdc","name":"Diffuse Glioma (TCGA GDC, 2025)","type_of_cancer_id":"difg","sample_count":530,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=difg_tcga_gdc"},{"cancer_study_identifier":"lgg_tcga","name":"Brain Lower Grade Glioma (TCGA, Firehose Legacy)","type_of_cancer_id":"difg","sample_count":530,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lgg_tcga"},{"cancer_study_identifier":"lgg_tcga_pan_can_atlas_2018","name":"Brain Lower Grade Glioma (TCGA, PanCancer Atlas)","type_of_cancer_id":"difg","sample_count":514,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lgg_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"difg_glass_2019","name":"Diffuse Glioma (GLASS Consortium, Nature 2019)","type_of_cancer_id":"difg","sample_count":444,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=difg_glass_2019"},{"cancer_study_identifier":"brain_cptac_2020","name":"Pediatric Brain Cancer (CPTAC/CHOP, Cell 2020)","type_of_cancer_id":"brain","sample_count":218,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=brain_cptac_2020"},{"cancer_study_identifier":"pcpg_tcga","name":"Pheochromocytoma and Paraganglioma (TCGA, Firehose Legacy)","type_of_cancer_id":"mnet","sample_count":184,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=pcpg_tcga"},{"cancer_study_identifier":"pcpg_tcga_pan_can_atlas_2018","name":"Pheochromocytoma and Paraganglioma (TCGA, PanCancer Atlas)","type_of_cancer_id":"soft_tissue","sample_count":178,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=pcpg_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"pcpg_tcga_pub","name":"Pheochromocytoma and Paraganglioma (TCGA, Cell 2017)","type_of_cancer_id":"soft_tissue","sample_count":178,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=pcpg_tcga_pub"},{"cancer_study_identifier":"hnsc_a5consortium_2025","name":"Hereditary SDHB-Mutant Pheochromocytomas and Paragangliomas (A5 Consortium, Nature Comm 2025)","type_of_cancer_id":"hnsc","sample_count":94,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=hnsc_a5consortium_2025"},{"cancer_study_identifier":"glioma_msk_2018","name":"Glioma (MSK, Nature 2019)","type_of_cancer_id":"difg","sample_count":91,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=glioma_msk_2018"},{"cancer_study_identifier":"difg_msk_2023","name":"IDH-mutated Diffuse Glioma (MSK, Clin Cancer Res 2024)","type_of_cance … (855 more chars)

▶ clickhouse_run_select_query
{
 "query": "SELECT 'lgg' AS s, * FROM gene_mutation_variants_in_study(study='lgg_tcga_pan_can_atlas_2018', gene='IDH1') ORDER BY altered_samples DESC LIMIT 8
UNION ALL
SELECT 'gbm' AS s, * FROM gene_mutation_variants_in_study(study='gbm_tcga_pan_can_atlas_2018', gene='IDH1') ORDER BY altered_samples DESC LIMIT 5"
}

◀ result
{"rows":[{"s":"lgg","mutation_variant":"R132H","mutation_type":"Missense_Mutation","altered_samples":358,"profiled_samples":514,"frequency_pct":69.6,"total_mutation_events":358},{"s":"lgg","mutation_variant":"R132C","mutation_type":"Missense_Mutation","altered_samples":17,"profiled_samples":514,"frequency_pct":3.3,"total_mutation_events":17},{"s":"lgg","mutation_variant":"R132G","mutation_type":"Missense_Mutation","altered_samples":11,"profiled_samples":514,"frequency_pct":2.1,"total_mutation_events":11},{"s":"lgg","mutation_variant":"R132S","mutation_type":"Missense_Mutation","altered_samples":9,"profiled_samples":514,"frequency_pct":1.8,"total_mutation_events":9},{"s":"gbm","mutation_variant":"R132H","mutation_type":"Missense_Mutation","altered_samples":22,"profiled_samples":397,"frequency_pct":5.5,"total_mutation_events":22},{"s":"gbm","mutation_variant":"R132G","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":397,"frequency_pct":0.5,"total_mutation_events":2},{"s":"gbm","mutation_variant":"R132C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":397,"frequency_pct":0.3,"total_mutation_events":1}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT 'lgg' AS s, * FROM gene_mutation_frequency_in_study(study='lgg_tcga_pan_can_atlas_2018', gene='IDH1')
UNION ALL SELECT 'gbm', * FROM gene_mutation_frequency_in_study(study='gbm_tcga_pan_can_atlas_2018', gene='IDH1')
UNION ALL SELECT 'glioma_mskcc_2019', * FROM gene_mutation_frequency_in_study(study='glioma_mskcc_2019', gene='IDH1')"
}

◀ result
{"rows":[{"s":"gbm","cancer_type":"Glioblastoma","altered_samples":25,"profiled_samples":397,"frequency_pct":6.3},{"s":"lgg","cancer_type":"Glioma","altered_samples":395,"profiled_samples":514,"frequency_pct":76.8},{"s":"glioma_mskcc_2019","cancer_type":"Glioma","altered_samples":339,"profiled_samples":1003,"frequency_pct":33.8}]}

▶ resolve_and_route
{
 "studyIds": [
  "lgg_tcga_pan_can_atlas_2018",
  "gbm_tcga_pan_can_atlas_2018"
 ]
}

◀ result
{"success":true,"message":"Found 2 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":2,"studiesWithMetadata":[{"studyId":"lgg_tcga_pan_can_atlas_2018","name":"Brain Lower Grade Glioma (TCGA, PanCancer Atlas)","sampleCount":514,"studyViewUrl":"https://www.cbioportal.org/study?id=lgg_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":["lgg_tcga_pan_can_atlas_2018_gistic","lgg_tcga_pan_can_atlas_2018_log2CNA","lgg_tcga_pan_can_atlas_2018_mutations","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","lgg_tcga_pan_can_atlas_2018_rppa","lgg_tcga_pan_can_atlas_2018_rppa_Zscores","lgg_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["lgg_tcga_pan_can_atlas_2018_armlevel_cna","lgg_tcga_pan_can_atlas_2018_genetic_ancestry","lgg_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","lgg_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","lgg_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"]}},{"studyId":"gbm_tcga_pan_can_atlas_2018","name":"Glioblastoma Multiforme (TCGA, PanCancer Atlas)","sampleCount":592,"studyViewUrl":"https://www.cbioportal.org/study?id=gbm_tcga_pan_can_atlas_2018","metadata":{"clinicalAttributeIds":["AGE","AJCC_PATH … (2213 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "lgg_tcga_pan_can_atlas_2018",
  "gbm_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "IDH1: MUT"
 ],
 "tab": "mutations",
 "profileFilter": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=lgg_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018&gene_list=IDH1%3A+MUT&case_set_id=all&profileFilter=mutations","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=lgg_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018&gene_list=IDH1%3A+MUT&case_set_id=all&profileFilter=mutations","data":{"studyIds":["lgg_tcga_pan_can_atlas_2018","gbm_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"lgg_tcga_pan_can_atlas_2018","name":"Brain Lower Grade Glioma (TCGA, PanCancer Atlas)","sampleCount":514},{"studyId":"gbm_tcga_pan_can_atlas_2018","name":"Glioblastoma Multiforme (TCGA, PanCancer Atlas)","sampleCount":592}],"genes":["IDH1"],"caseSetId":"all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

▶ navigate_to_study_view
{
 "studyIds": [
  "lgg_tcga_pan_can_atlas_2018",
  "gbm_tcga_pan_can_atlas_2018"
 ],
 "filterJson": {
  "geneFilters": [
   {
    "molecularProfileIds": [
     "lgg_tcga_pan_can_atlas_2018_mutations",
     "gbm_tcga_pan_can_atlas_2018_mutations"
    ],
    "geneQueries": [
     [
      {
       "hugoGeneSymbol": "IDH1"
      }
     ]
    ]
   }
  ]
 }
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/study/summary?id=lgg_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018#filterJson=%7B%22geneFilters%22%3A%5B%7B%22geneQueries%22%3A%5B%5B%7B%22hugoGeneSymbol%22%3A%22IDH1%22%7D%5D%5D%2C%22molecularProfileIds%22%3A%5B%22gbm_tcga_pan_can_atlas_2018_mutations%22%2C%22lgg_tcga_pan_can_atlas_2018_mutations%22%5D%7D%5D%7D","url":"https://www.cbioportal.org/study/summary?id=lgg_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018#filterJson=%7B%22geneFilters%22%3A%5B%7B%22geneQueries%22%3A%5B%5B%7B%22hugoGeneSymbol%22%3A%22IDH1%22%7D%5D%5D%2C%22molecularProfileIds%22%3A%5B%22gbm_tcga_pan_can_atlas_2018_mutations%22%2C%22lgg_tcga_pan_can_atlas_2018_mutations%22%5D%7D%5D%7D","data":{"studyIds":["lgg_tcga_pan_can_atlas_2018","gbm_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"lgg_tcga_pan_can_atlas_2018","name":"Brain Lower Grade Glioma (TCGA, PanCancer Atlas)","sampleCount":514},{"studyId":"gbm_tcga_pan_can_atlas_2018","name":"Glioblastoma Multiforme (TCGA, PanCancer Atlas)","sampleCount":592}],"tab":"summary","hasFilters":true,"hasPlotsConfig":false,"pageDescription":"Overview of all study data displayed as interactive charts summarizing available clinical and genomic data. Click within a chart to filter. Additional charts may be available in the Charts menu."}}

═ answer (success)
## IDH1 mutations in glioma

I used the TCGA PanCancer Atlas cohorts as the reference. The numbers are sample-level, and the denominator is the samples profiled for IDH1.

| Cohort | IDH1-mutated / profiled | Frequency |
|---|---|---|
| [Lower Grade Glioma (TCGA PanCancer Atlas)](https://www.cbioportal.org/study/summary?id=lgg_tcga_pan_can_atlas_2018) | 395 / 514 | 76.8% |
| [Glioblastoma (TCGA PanCancer Atlas)](https://www.cbioportal.org/study/summary?id=gbm_tcga_pan_can_atlas_2018) | 25 / 397 | 6.3% |

**Which variants occur** (samples with each variant):

- **Lower grade glioma (514 profiled):**
  - R132H: 358 (69.6%)
  - R132C: 17 (3.3%)
  - R132G: 11 (2.1%)
  - R132S: 9 (1.8%)
- **Glioblastoma (397 profiled):**
  - R132H: 22 (5.5%)
  - R132G: 2 (0.5%)
  - R132C: 1 (0.3%)

- **Hotspot:** In both cohorts, every IDH1 variant listed is a missense change at codon R132. R132H accounts for most of them.
- **Grade:** IDH1 mutations are common in lower grade glioma and uncommon in glioblastoma.
- **Other cohorts:** The frequency depends on how a cohort was assembled. In the [MSK Glioma cohort (Clin Cancer Res 2019)](https://www.cbioportal.org/study/summary?id=glioma_mskcc_2019), IDH1 is mutated in 339 of 1,003 samples (33.8%).
- **Driver status:** I didn't check driver or oncogenicity annotations. These counts are all IDH1 mutations, not only annotated drivers.

**Explore in cBioPortal**

- [IDH1 Mutations tab (lollipop plot and mutation table), lower grade glioma and glioblastoma](https://www.cbioportal.org/results/mutations?cancer_study_list=lgg_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018&gene_list=IDH1%3A+MUT&case_set_id=all&profileFilter=mutations)
- [Cohort overview filtered to IDH1-mutated samples](https://www.cbioportal.org/study/summary?id=lgg_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018#filterJson=%7B%22geneFilters%22%3A%5B%7B%22geneQueries%22%3A%5B%5B%7B%22hugoGeneSymbol%22%3A%22IDH1%22%7D%5D%5D%2C%22molecularProfileIds%22%3A%5B%22gbm_tcga_pan_can_atlas_2018_mutations%22%2C%22lgg_tcga_pan_can_atlas_2018_mutations%22%5D%7D%5D%7D)

Several other glioma studies are available, including the GLASS consortium, TCGA Firehose Legacy and GDC, and the MSK IDH-mutant diffuse glioma cohort. I can run the same analysis on any of them. I can also look at co-occurring alterations such as TP53, ATRX, CIC or 1p/19q, or at survival by IDH1 status.