Q (sonnet): Find patients IDs and samples in colorectal cancer that harbor the V600V alteration in BRAF

▶ read_guide
{
 "uri": "cbioportal://common-pitfalls#16"
}

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

◀ result
### 16. 🚨 SILENT QUERY SUBSTITUTION ("did you mean...")

When the user's wording differs from canonical terminology (e.g. "V600V" looks like "V600E" with a typo, or "point mutation" sounds like "missense"), it is forbidden to silently rewrite the question and answer the rewritten version. Doing so produces an answer that looks confident but is for a different question — the user cannot tell what was changed.

#### ❌ Wrong: silently substitute

> User: *"Find patients in colorectal cancer with the V600V alteration in BRAF"*
> Agent: *(internally treats this as V600E)* "I found 412 samples with BRAF V600E in colorectal studies..."

> User: *"What is the most prevalent TP53 mutation in uterine cancer that is not a point mutation?"*
> Agent: *(internally treats "point mutation" = "missense", silently excludes only missense)* "The most prevalent non-missense TP53 mutation is..."

#### ✅ Correct: answer the literal question, flag any normalization

For an unusual-looking variant the user may have typed deliberately:
- Query for what was asked, literally.
- If 0 rows come back, **explain *why* zero is the expected answer** before suggesting a likely-intended alternative. For synonymous variants (e.g. BRAF V600V, TP53 R175R), the explanation is: *cBioPortal's mutation tables filter out synonymous (silent) variants in most studies, so 0 hits means "filtered upstream", not "no such variant exists in any patient"*. Then ask: *"Did you mean V600E (the canonical activating variant)? Or would you like me to look for V600V in the studies that do retain synonymous calls?"*
- If the wording is ambiguous (e.g. "point mutation"), ask the user which definition they meant before querying — do not pick one silently.

#### Mutation-type terminology mapping (use this to disambiguate)

| User says | Canonical definition | `mutation_type` filter |
|---|---|---|
| "point mutation" | Any SNV (single-nucleotide variant) — includes missense, nonsense, synonymous, splice-site SNVs | `mutation_type IN ('Missense_Mutation','Nonsense_Mutation','Silent','Splice_Site')` — **but ask the user to confirm scope first** |
| "missense" | Single amino-acid substitution that changes the protein | `mutation_type = 'Missense_Mutation'` |
| "nonsense" / "stop-gain" | Premature stop codon | `mutation_type = 'Nonsense_Mutation'` |
| "synonymous" / "silent" | Nucleotide change with no amino-acid change | `mutation_type = 'Silent'` (**often filtered out of public datasets** — see below) |
| "splice site" | Mutation in canonical splice acceptor/donor | `mutation_type = 'Splice_Site'` |
| "frameshift" | Indel changing reading frame | `mutation_type IN ('Frame_Shift_Ins','Frame_Shift_Del')` |
| "indel" / "in-frame" | In-frame insertion or deletion | `mutation_type IN ('In_Frame_Ins','In_Frame_Del')` |
| "truncating" | Anything that disrupts the protein early | `mutation_type IN ('Nonsense_Mutation','Frame_Shift_Ins','Frame_Shift_Del','Splice_Site','Nonstop_Mutation')` |

**Synonymous-variant filter. … (785 more chars)

◀ 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)

▶ search_oncotree
{
 "search_term": "colorectal"
}

▶ list_studies
{
 "search": "colorectal",
 "limit": 30
}

◀ result
{"result":[{"code":"COADREAD","name":"Colorectal Adenocarcinoma","score":60,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD"},{"code":"CAIS","name":"Colon Adenocarcinoma In Situ","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > CAIS"},{"code":"CMC","name":"Medullary Carcinoma of the Colon","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > CMC"},{"code":"COAD","name":"Colon Adenocarcinoma","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > COAD"},{"code":"MACR","name":"Mucinous Adenocarcinoma of the Colon and Rectum","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > MACR"},{"code":"READ","name":"Rectal Adenocarcinoma","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > READ"},{"code":"SRCCR","name":"Signet Ring Cell Adenocarcinoma of the Colon and Rectum","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > SRCCR"}]}

◀ result
{"result":[{"cancer_study_identifier":"msk_met_2021","name":"MSK MetTropism (MSK, Cell 2021)","type_of_cancer_id":"mixed","sample_count":25775,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=msk_met_2021"},{"cancer_study_identifier":"crc_msk_2026","name":"Colorectal Adenocarcinoma (MSK, 2026)","type_of_cancer_id":"read","sample_count":7237,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=crc_msk_2026"},{"cancer_study_identifier":"crc_eo_2020","name":"Colorectal Cancer (MSK, JNCI 2021)","type_of_cancer_id":"bowel","sample_count":1516,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=crc_eo_2020"},{"cancer_study_identifier":"crc_msk_2017","name":"Metastatic Colorectal Cancer (MSK, Cancer Cell 2018)","type_of_cancer_id":"coadread","sample_count":1134,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=crc_msk_2017"},{"cancer_study_identifier":"crc_sysucc_2022","name":"Colorectal Cancer- ChangKang Project (SYSUCC, Nat Commun 2022)","type_of_cancer_id":"coadread","sample_count":1015,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=crc_sysucc_2022"},{"cancer_study_identifier":"coadread_tcga","name":"Colorectal Adenocarcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"coadread","sample_count":640,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=coadread_tcga"},{"cancer_study_identifier":"coadread_dfci_2016","name":"Colorectal Adenocarcinoma (DFCI, Cell Reports 2016)","type_of_cancer_id":"coadread","sample_count":619,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=coadread_dfci_2016"},{"cancer_study_identifier":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"coadread","sample_count":594,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=coadread_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"crc_apc_impact_2020","name":"Colorectal Cancer (MSK, Gastroenterology 2020)","type_of_cancer_id":"coadread","sample_count":471,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=crc_apc_impact_2020"},{"cancer_study_identifier":"coadread_tcga_pub","name":"Colorectal Adenocarcinoma (TCGA, Nature 2012)","type_of_cancer_id":"coadread","sample_count":276,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=coadread_tcga_pub"},{"cancer_study_identifier":"bowel_colitis_msk_2022","name":"Colorectal Adenocarcinoma (MSK, Nat Commun 2022)","type_of_cancer_id":"bowel","sample_count":179,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=bowel_colitis_msk_2022"},{"cancer_study_identifier":"coadread_cass_2020","name":"Colorectal Cancer (CAS Shanghai, Cancer Cell 2020)","type_of_cancer_id":"coadread","sample_count":146,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=coadread_cass_2020"},{"cancer_study_identifier":"coadread_mskcc","name":"Colorectal Adenocarcinoma Triplets (MSK, Geno … (2148 more chars)

▶ clickhouse_list_table_columns
{
 "table": "genomic_event_derived"
}

◀ result
{"columns":[{"name":"sample_unique_id","type":"String"},{"name":"hugo_gene_symbol","type":"String","comment":"HUGO gene symbol (e.g., TP53, KRAS, BRAF). Use for gene-specific queries."},{"name":"entrez_gene_id","type":"Int32"},{"name":"gene_panel_stable_id","type":"LowCardinality(String)"},{"name":"cancer_study_identifier","type":"LowCardinality(String)"},{"name":"genetic_profile_stable_id","type":"LowCardinality(String)"},{"name":"variant_type","type":"LowCardinality(String)","comment":"Type of genomic event: \"mutation\" for SNVs/indels, \"cna\" for copy number alterations, \"structural_variant\" for SVs. Always filter by this."},{"name":"mutation_variant","type":"String","comment":"Protein change notation (e.g., p.V600E, p.R175H). Use for specific variant queries. \"NA\" for non-mutation events."},{"name":"mutation_type","type":"LowCardinality(String)"},{"name":"mutation_status","type":"LowCardinality(String)","comment":"For mutations: Somatic, Germline, UNKNOWN, or UNCALLED. Filter mutation_status != \"UNCALLED\" to exclude uncertain calls. Include all other statuses."},{"name":"driver_filter","type":"LowCardinality(String)"},{"name":"driver_filter_annotation","type":"String"},{"name":"driver_tiers_filter","type":"LowCardinality(String)"},{"name":"driver_tiers_filter_annotation","type":"String"},{"name":"cna_alteration","type":"Nullable(Int8)","comment":"Copy number alteration: only 2 = amplification (AMP) and -2 = deep deletion (HOMDEL) are stored. Shallow deletion (-1), diploid (0) and gain (1) are not in this table; query genetic_alteration_derived WHERE profile_type = 'gistic' (alteration_value is a String, e.g. '-1'). NULL for non-CNA events."},{"name":"cna_cytoband","type":"String"},{"name":"sv_event_info","type":"String"},{"name":"patient_unique_id","type":"String"},{"name":"off_panel","type":"Bool","comment":"Boolean: 1 = mutation outside gene panel coverage (off-panel), 0 = within panel (on-panel). Filter off_panel = 0 for reliable frequency calculations."}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT cancer_study_identifier, type_of_cancer_id FROM cancer_study WHERE type_of_cancer_id IN ('coadread','coad','read','caism','cmc','macr','srccr','cais') ORDER BY cancer_study_identifier"
}

◀ result
{"rows":[{"cancer_study_identifier":"coad_caseccc_2015","type_of_cancer_id":"coad"},{"cancer_study_identifier":"coad_cptac_2019","type_of_cancer_id":"coad"},{"cancer_study_identifier":"coad_cptac_gdc","type_of_cancer_id":"coad"},{"cancer_study_identifier":"coad_silu_2022","type_of_cancer_id":"coad"},{"cancer_study_identifier":"coad_tcga_gdc","type_of_cancer_id":"coad"},{"cancer_study_identifier":"coadread_cass_2020","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_dfci_2016","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_genentech","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_mskcc","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_mskresistance_2022","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_tcga","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_tcga_pan_can_atlas_2018","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"coadread_tcga_pub","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_apc_impact_2020","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_dd_2022","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_hta11_htan_2021","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_hta8_htan_2024","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_msk_2017","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_msk_2026","type_of_cancer_id":"read"},{"cancer_study_identifier":"crc_nigerian_2020","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"crc_sysucc_2022","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"read_tcga_gdc","type_of_cancer_id":"read"},{"cancer_study_identifier":"rectal_msk_2019","type_of_cancer_id":"coadread"},{"cancer_study_identifier":"rectal_radiation_msk_2024","type_of_cancer_id":"read"}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT cancer_study_identifier, patient_unique_id, sample_unique_id, hugo_gene_symbol, mutation_variant, mutation_type, mutation_status
FROM genomic_event_derived
WHERE variant_type = 'mutation'
  AND hugo_gene_symbol = 'BRAF'
  AND (mutation_variant = 'p.V600V' OR mutation_variant = 'V600V')
ORDER BY cancer_study_identifier
"
}

◀ result
{"rows":[]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT mutation_type, count() AS n
FROM genomic_event_derived
WHERE variant_type = 'mutation' AND hugo_gene_symbol = 'BRAF'
GROUP BY mutation_type
ORDER BY n DESC
"
}

◀ result
{"rows":[{"mutation_type":"Missense_Mutation","n":15842},{"mutation_type":"In_Frame_Del","n":284},{"mutation_type":"Frame_Shift_Del","n":229},{"mutation_type":"Nonsense_Mutation","n":219},{"mutation_type":"Frame_Shift_Ins","n":140},{"mutation_type":"Splice_Site","n":125},{"mutation_type":"In_Frame_Ins","n":108},{"mutation_type":"Splice_Region","n":45},{"mutation_type":"frameshift_deletion","n":1}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT cancer_study_identifier, hugo_gene_symbol, mutation_variant, count() AS n
FROM genomic_event_derived
WHERE variant_type = 'mutation' AND mutation_type = 'Silent' AND hugo_gene_symbol = 'BRAF'
GROUP BY cancer_study_identifier, hugo_gene_symbol, mutation_variant
ORDER BY n DESC
LIMIT 20
"
}

◀ result
{"rows":[]}

═ answer (success)
This confirms it clearly: across the **entire database** (not just colorectal studies), there is not a single `Silent`-type BRAF mutation record. All BRAF mutation types present are Missense, In_Frame_Del/Ins, Frame_Shift_Del/Ins, Nonsense, and Splice_Site/Region — no synonymous calls at all.

## Result

I searched literally for **BRAF V600V** (the synonymous/silent variant — codon 600 remains Valine, no amino-acid change) across all colorectal cancer cohorts in cBioPortal, and found **0 patients and 0 samples**.

This is not because the variant doesn't occur biologically — it's because cBioPortal's mutation pipeline filters out synonymous (silent) calls upstream of the database in essentially all studies. I confirmed this isn't specific to colorectal cancer: across the **entire cBioPortal database**, there is not a single `Silent`-type mutation recorded for BRAF in any study. Only non-synonymous types are retained (Missense, Nonsense, Frame_Shift, In_Frame, Splice_Site/Region).

So "0 hits" here means **filtered upstream**, not **"this variant never occurs in any patient's tumor."**

**Did you mean BRAF V600E** — the canonical activating driver mutation, present in a well-known subset (~10-15%) of colorectal adenocarcinomas, particularly MSI-high/right-sided tumors? If so, I can look that up in a specific colorectal cohort (e.g., TCGA PanCancer Atlas or a pooled colorectal set) and generate the corresponding patient/sample list and OncoPrint link.

Alternatively, if you specifically need the true synonymous V600V call and know it exists in a raw MAF file outside this filtered database, that data would not be retrievable from cBioPortal itself.

Let me know which you'd like — I won't substitute one for the other without your confirmation.