Q (sonnet): show me point mutations in EGFR in lung cancer

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

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### 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)

═ answer (success)
"Point mutation" is ambiguous — per the terminology guide, it could mean:

1. **Broadly**, any single-nucleotide variant (SNV): missense, nonsense, silent, and splice-site substitutions
2. **Narrowly**, just missense mutations (single amino-acid substitutions) — this is the most common colloquial usage

Before I query, which scope did you mean?

- **All SNV types** (missense + nonsense + silent + splice-site)
- **Missense only** (most common interpretation — single amino-acid changes)

Also, for "lung cancer" — did you have a specific study in mind (e.g., TCGA lung adenocarcinoma, TCGA lung squamous, or a larger MSK pan-lung cohort), or would you like me to look across all lung cancer studies in cBioPortal?