Q (haiku): show me P135L mutations in $p14^{ARF}$

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

▶ clickhouse_list_tables
{}

◀ 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
{"tables":[{"name":"allele_specific_copy_number"},{"name":"alteration_driver_annotation"},{"name":"cancer_study"},{"name":"cancer_study_query_preferences"},{"name":"cancer_study_tags"},{"name":"cbioportal_sequence_state"},{"name":"clinical_attribute_counts"},{"name":"clinical_attribute_meta"},{"name":"clinical_data_derived"},{"name":"clinical_event"},{"name":"clinical_event_data"},{"name":"clinical_event_data_derived"},{"name":"clinical_event_derived"},{"name":"clinical_patient"},{"name":"clinical_sample"},{"name":"cna_event"},{"name":"cna_panel_gene_coverage"},{"name":"cna_wes_coverage"},{"name":"co_altered_genes_in_study"},{"name":"copy_number_seg"},{"name":"copy_number_seg_file"},{"name":"gene"},{"name":"gene_alias"},{"name":"gene_alteration_frequency_by_cancer_type"},{"name":"gene_cna_distribution_in_study"},{"name":"gene_mutation_frequency_by_cancer_type"},{"name":"gene_mutation_frequency_in_studies"},{"name":"gene_mutation_frequency_in_study"},{"name":"gene_mutation_variants_in_study"},{"name":"gene_pair_coexpression"},{"name":"gene_panel"},{"name":"gene_panel_list"},{"name":"gene_panel_to_gene_derived"},{"name":"generic_assay_data_derived"},{"name":"generic_assay_meta_derived"},{"name":"generic_assay_profile_entity_derived"},{"name":"generic_entity_properties"},{"name":"geneset"},{"name":"geneset_gene"},{"name":"geneset_hierarchy_leaf"},{"name":"geneset_hierarchy_node"},{"name":"genetic_alteration"},{"name":"genetic_alteration_derived"},{"name":"genetic_entity"},{"name":"genetic_profile"},{"name":"genetic_profile_link"},{"name":"genetic_profile_samples"},{"name":"genomic_event_derived"},{"name":"gistic"},{"name":"gistic_to_gene"},{"name":"info"},{"name":"mut_sig"},{"name":"mutation"},{"name":"mutation_count_by_keyword"},{"name":"mutation_derived"},{"name":"mutation_event"},{"name":"mutation_panel_gene_coverage"},{"name":"mutation_wes_coverage"},{"name":"patient"},{"name":"reference_genome"},{"name":"reference_genome_gene"},{"name":"resource_definition"},{"name":"resource_patient"},{"name":"resource_sample"},{"name":"resource_study"},{"name":"sample"},{"name":"sample_cna_event"},{"name":"sample_derived"},{"name":"sample_list"},{"name":"sample_list_list"},{"name":"sample_profile"},{"name":"sample_to_gene_panel_derived"},{"name":"structural_variant"},{"name":"sv_panel_gene_coverage"},{"name":"sv_wes_coverage"},{"name":"top_cna_genes_in_study"},{"name":"top_mutated_genes_in_cohort"},{"name":"top_mutated_genes_in_study"},{"name":"top_sv_genes_in_study"},{"name":"treatment_counts_in_study"},{"name":"treatment_regimens_in_study"},{"name":"type_of_cancer"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT hugo_gene_symbol FROM gene WHERE hugo_gene_symbol IN ('CDKN2A', 'ARF') OR lower(hugo_gene_symbol) LIKE '%arf%' LIMIT 10"
}

◀ result
{"rows":[{"hugo_gene_symbol":"ARF1"},{"hugo_gene_symbol":"ARF3"},{"hugo_gene_symbol":"ARF4"},{"hugo_gene_symbol":"ARF4P1"},{"hugo_gene_symbol":"ARF5"},{"hugo_gene_symbol":"ARF6"},{"hugo_gene_symbol":"CDKN2A"},{"hugo_gene_symbol":"SCARF1"},{"hugo_gene_symbol":"MARF1"},{"hugo_gene_symbol":"ARFRP1"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT
    cancer_study_identifier,
    sample_unique_id,
    patient_unique_id,
    hugo_gene_symbol,
    mutation_variant,
    mutation_type,
    mutation_status,
    tumor_seq_allele1,
    tumor_seq_allele2
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'CDKN2A'
  AND variant_type = 'mutation'
  AND mutation_variant = 'P135L'
  AND mutation_status != 'UNCALLED'
ORDER BY cancer_study_identifier, sample_unique_id",
 "max_rows": 1000
}

◀ result
{"error_message":"Query execution failed: HTTPDriver for https://dl96orhu96.us-east-1.aws.clickhouse.cloud:8443 received ClickHouse error code 47\n Code: 47. DB::Exception: Unknown expression identifier `tumor_seq_allele1` in scope SELECT cancer_study_identifier, sample_unique_id, patient_unique_id, hugo_gene_symbol, mutation_variant, mutation_type, mutation_status, tumor_seq_allele1, tumor_seq_allele2 FROM genomic_event_derived WHERE (hugo_gene_symbol = 'CDKN2A') AND (variant_type = 'mutation') AND (mutation_variant = 'P135L') AND (mutation_status != 'UNCALLED') ORDER BY cancer_study_identifier ASC, sample_unique_id ASC. (UNKNOWN_IDENTIFIER) (version 26.4.1.2359 (official build))\n"}

▶ 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,
    sample_unique_id,
    patient_unique_id,
    hugo_gene_symbol,
    mutation_variant,
    mutation_type,
    mutation_status
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'CDKN2A'
  AND variant_type = 'mutation'
  AND mutation_variant = 'P135L'
  AND mutation_status != 'UNCALLED'
ORDER BY cancer_study_identifier, sample_unique_id",
 "max_rows": 1000
}

◀ result
{"rows":[]}

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT mutation_variant FROM genomic_event_derived
WHERE hugo_gene_symbol = 'CDKN2A'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
  AND mutation_variant LIKE 'P135%'
LIMIT 100"
}

◀ result
{"rows":[{"mutation_variant":"P135S"},{"mutation_variant":"P135Q"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT
    mutation_variant,
    mutation_type,
    COUNT(DISTINCT sample_unique_id) AS sample_count,
    COUNT(DISTINCT cancer_study_identifier) AS study_count
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'CDKN2A'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
  AND mutation_variant LIKE 'P135%'
GROUP BY mutation_variant, mutation_type
ORDER BY sample_count DESC"
}

◀ result
{"rows":[{"mutation_variant":"P135S","mutation_type":"Missense_Mutation","sample_count":8,"study_count":7},{"mutation_variant":"P135Q","mutation_type":"Missense_Mutation","sample_count":5,"study_count":1}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT
    cancer_study_identifier,
    sample_unique_id,
    patient_unique_id,
    hugo_gene_symbol,
    mutation_variant,
    mutation_type,
    mutation_status
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'CDKN2A'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
  AND mutation_variant IN ('P135S', 'P135Q')
ORDER BY mutation_variant DESC, cancer_study_identifier, sample_unique_id",
 "max_rows": 100
}

◀ result
{"rows":[{"cancer_study_identifier":"ccle_broad_2019","sample_unique_id":"ccle_broad_2019_MEWO_SKIN","patient_unique_id":"ccle_broad_2019_MEWO_SKIN","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"NA"},{"cancer_study_identifier":"hnsc_tcga","sample_unique_id":"hnsc_tcga_TCGA-H7-8501-01","patient_unique_id":"hnsc_tcga_TCGA-H7-8501","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"Somatic"},{"cancer_study_identifier":"mel_mskimpact_2020","sample_unique_id":"mel_mskimpact_2020_P-0001251-T01-IM3","patient_unique_id":"mel_mskimpact_2020_P-0001251","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"SOMATIC"},{"cancer_study_identifier":"msk_impact_2017","sample_unique_id":"msk_impact_2017_P-0001251-T01-IM3","patient_unique_id":"msk_impact_2017_P-0001251","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"NA"},{"cancer_study_identifier":"msk_met_2021","sample_unique_id":"msk_met_2021_P-0001251-T01-IM3","patient_unique_id":"msk_met_2021_P-0001251","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"SOMATIC"},{"cancer_study_identifier":"msk_met_2021","sample_unique_id":"msk_met_2021_P-0015894-T01-IM6","patient_unique_id":"msk_met_2021_P-0015894","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"SOMATIC"},{"cancer_study_identifier":"skcm_broad","sample_unique_id":"skcm_broad_MEL-JWCI-WGS-1","patient_unique_id":"skcm_broad_MEL-JWCI-WGS-1","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"NA"},{"cancer_study_identifier":"skcm_tcga","sample_unique_id":"skcm_tcga_TCGA-D3-A2JF-06","patient_unique_id":"skcm_tcga_TCGA-D3-A2JF","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135S","mutation_type":"Missense_Mutation","mutation_status":"Somatic"},{"cancer_study_identifier":"pancan_pdmr_2025","sample_unique_id":"pancan_pdmr_2025_524724-177-R-QQE","patient_unique_id":"pancan_pdmr_2025_P-524724","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135Q","mutation_type":"Missense_Mutation","mutation_status":"NA"},{"cancer_study_identifier":"pancan_pdmr_2025","sample_unique_id":"pancan_pdmr_2025_524724-177-R-QQEM174","patient_unique_id":"pancan_pdmr_2025_P-524724","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135Q","mutation_type":"Missense_Mutation","mutation_status":"NA"},{"cancer_study_identifier":"pancan_pdmr_2025","sample_unique_id":"pancan_pdmr_2025_524724-177-R-QQEM178M935","patient_unique_id":"pancan_pdmr_2025_P-524724","hugo_gene_symbol":"CDKN2A","mutation_variant":"P135Q","mutation_type":"Missense_Mutation","mutation_status":"NA"},{"cancer_study_identifier":"pancan_pdmr_2025","sample_unique_id":"pancan_pdmr_2025_524724-177-R-QQEM180SUZ","patient_uniqu … (418 more chars)

═ answer (success)
## Summary

**P135L mutations in p14^ARF (CDKN2A) were not found in the cBioPortal database.** However, the database does contain other mutations at position 135 of CDKN2A:

### Mutations Found at CDKN2A Position 135

| Variant | Type | Sample Count | Study Count | Details |
|---------|------|-------------|------------|---------|
| **P135S** | Missense | 8 samples | 7 studies | Serine substitution (common in MSK and TCGA data) |
| **P135Q** | Missense | 5 samples | 1 study | Glutamine substitution (all from pancan_pdmr_2025 study) |

### P135S Samples (8 total)
- **ccle_broad_2019**: MEWO (melanoma)
- **hnsc_tcga**: TCGA-H7-8501 (head/neck squamous cell carcinoma)
- **mel_mskimpact_2020** & **msk_impact_2017**: P-0001251 (melanoma, same patient)
- **msk_met_2021**: 2 samples (P-0001251, P-0015894)
- **skcm_broad**: MEL-JWCI-WGS-1 (melanoma)
- **skcm_tcga**: TCGA-D3-A2JF (melanoma)

### P135Q Samples (5 total, all from pancan_pdmr_2025)
- All 5 samples are from patient P-524724 (multiple timepoints/biopsies)

**Note:** p14^ARF is an upstream in-frame translation product from the CDKN2A locus (p16INK4a alternative reading frame). The P135 position refers to the p14^ARF protein sequence. The absence of P135L may indicate it is either not present in these public datasets or is a very rare variant.