Q (sonnet-5.5): what is the most prevalent TP53 mutation in uterine cancer that is not a point mutation

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

◀ 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)

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

▶ search_oncotree
{
 "search_term": "uterine"
}

◀ 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)

◀ result
{"result":[{"code":"OUSARC","name":"Uterine Sarcoma, Other","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > OUSARC"},{"code":"UAS","name":"Uterine Adenosarcoma","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > UAS"},{"code":"UASC","name":"Uterine Adenosquamous Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UASC"},{"code":"UCCC","name":"Uterine Clear Cell Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UCCC"},{"code":"UCS","name":"Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UCS"},{"code":"UDDC","name":"Uterine Dedifferentiated Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UDDC"},{"code":"UEC","name":"Uterine Endometrioid Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UEC"},{"code":"UELMS","name":"Uterine Epithelioid Leiomyosarcoma","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > USMT > UELMS"},{"code":"ULM","name":"Uterine Leiomyoma","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > USMT > ULM"},{"code":"ULMS","name":"Uterine Leiomyosarcoma","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > USMT > ULMS"},{"code":"UMC","name":"Uterine Mucinous Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UMC"},{"code":"UMEC","name":"Uterine Mixed Endometrial Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UMEC"},{"code":"UMLMS","name":"Uterine Myxoid Leiomyosarcoma","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > USMT > UMLMS"},{"code":"UMNC","name":"Uterine Mesonephric Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UMNC"},{"code":"UNEC","name":"Uterine Neuroendocrine Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > UNEC"},{"code":"UPECOMA","name":"Uterine Perivascular Epithelioid Cell Tumor","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > UPECOMA"},{"code":"USARC","name":"Uterine Sarcoma/Mesenchymal","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC"},{"code":"USC","name":"Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma","score":60,"mainType":"Endometrial Cancer","tissue":"Uterus","hierarchy":"UTERUS > UCEC > USC"},{"code":"USMT","name":"Uterine Smooth Muscle Tumor","score":60,"mainType":"Uterine Sarcoma","tissue":"Uterus","hierarchy":"UTERUS > USARC > USMT"},{"code":"USTUMP","name":"Uterine Smooth Muscle Tumor of Un … (883 more chars)

═ answer (success)
Two parts of your question can be read more than one way, so I'd like to confirm them before I run anything.

**1. What counts as a "point mutation"?**
- **(a) Missense only.** This excludes only single amino-acid substitutions. The "not a point mutation" answer would then come from nonsense, frameshift, splice-site, and in-frame indel calls.
- **(b) Any single-nucleotide change.** This excludes missense, nonsense, and splice-site SNVs. What remains would be frameshift and in-frame insertions and deletions.
- **(c) Something else.** For example, you might mean only truncating events, or copy-number and structural events.

**2. What do you mean by "uterine cancer"?**
- **Endometrial carcinoma (UCEC).** I'd use the TCGA PanCancer Atlas uterine corpus endometrial carcinoma study, which is the usual reference cohort. I could also use the MSK-IMPACT or MSK-CHORD uterine samples.
- **Uterine carcinosarcoma (UCS) or uterine sarcomas.** These are separate diseases and would give a different answer.
- **All of the above pooled.**

If you have no preference, I'll use option (a) with the TCGA PanCancer Atlas endometrial study, counting patients. I'll state those choices in the answer and link the matching view in cBioPortal.