Q (sonnet-5.5): How many samples are there that have any of these mutations in SEPHS1: p.Arg371Trp, p.Arg371Gln, p.Arg371Gly?

▶ 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)

▶ clickhouse_run_select_query
{
 "query": "SELECT cancer_study_identifier, mutation_variant, count(DISTINCT sample_unique_id) AS samples FROM genomic_event_derived WHERE variant_type='mutation' AND mutation_status != 'UNCALLED' AND hugo_gene_symbol='SEPHS1' AND mutation_variant IN ('R371W','R371Q','R371G') GROUP BY cancer_study_identifier, mutation_variant ORDER BY cancer_study_identifier"
}

◀ result
{"rows":[{"cancer_study_identifier":"coad_cptac_gdc","mutation_variant":"R371Q","samples":1},{"cancer_study_identifier":"coad_tcga_gdc","mutation_variant":"R371Q","samples":1},{"cancer_study_identifier":"coadread_tcga","mutation_variant":"R371Q","samples":2},{"cancer_study_identifier":"coadread_tcga_pan_can_atlas_2018","mutation_variant":"R371Q","samples":1},{"cancer_study_identifier":"coadread_tcga_pub","mutation_variant":"R371Q","samples":2},{"cancer_study_identifier":"mel_dfci_2019","mutation_variant":"R371W","samples":1},{"cancer_study_identifier":"mel_iatlas_liu_2019","mutation_variant":"R371W","samples":1},{"cancer_study_identifier":"ohnca_cptac_gdc","mutation_variant":"R371Q","samples":1},{"cancer_study_identifier":"pancan_pcawg_2020","mutation_variant":"R371Q","samples":1}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT cancer_study_identifier, mutation_variant, count(DISTINCT sample_unique_id) AS samples FROM genomic_event_derived WHERE variant_type='mutation' AND mutation_status != 'UNCALLED' AND hugo_gene_symbol='SEPHS1' AND mutation_variant IN ('R371W','R371Q','R371G') AND cancer_study_identifier IN (SELECT cancer_study_identifier FROM cancer_study_query_preferences WHERE preference_name='all_studies_non_redundant') GROUP BY cancer_study_identifier, mutation_variant ORDER BY cancer_study_identifier"
}

◀ result
{"rows":[{"cancer_study_identifier":"coadread_tcga_pan_can_atlas_2018","mutation_variant":"R371Q","samples":1},{"cancer_study_identifier":"mel_dfci_2019","mutation_variant":"R371W","samples":1},{"cancer_study_identifier":"pancan_pcawg_2020","mutation_variant":"R371Q","samples":1}]}

▶ resolve_and_route
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018",
  "mel_dfci_2019",
  "pancan_pcawg_2020"
 ]
}

◀ result
{"success":true,"message":"Found 3 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":3,"studiesWithMetadata":[{"studyId":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":594,"studyViewUrl":"https://www.cbioportal.org/study?id=coadread_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":["coadread_tcga_pan_can_atlas_2018_gistic","coadread_tcga_pan_can_atlas_2018_log2CNA","coadread_tcga_pan_can_atlas_2018_mutations","coadread_tcga_pan_can_atlas_2018_protein_quantification","coadread_tcga_pan_can_atlas_2018_protein_quantification_zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","coadread_tcga_pan_can_atlas_2018_rppa","coadread_tcga_pan_can_atlas_2018_rppa_Zscores","coadread_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["coadread_tcga_pan_can_atlas_2018_armlevel_cna","coadread_tcga_pan_can_atlas_2018_genetic_ancestry","coadread_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","coadread_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["coadread_tcga_pan_can_atlas_2018_protein_quantification_zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","coadread_tcga_pan_can_atlas_2018_rp … (3308 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018",
  "mel_dfci_2019",
  "pancan_pcawg_2020"
 ],
 "genes": [
  "SEPHS1: MUT = R371W MUT = R371Q MUT = R371G"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018%2Cmel_dfci_2019%2Cpancan_pcawg_2020&gene_list=SEPHS1%3A+MUT+%3D+R371W+MUT+%3D+R371Q+MUT+%3D+R371G&case_set_id=all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018%2Cmel_dfci_2019%2Cpancan_pcawg_2020&gene_list=SEPHS1%3A+MUT+%3D+R371W+MUT+%3D+R371Q+MUT+%3D+R371G&case_set_id=all","data":{"studyIds":["coadread_tcga_pan_can_atlas_2018","mel_dfci_2019","pancan_pcawg_2020"],"studies":[{"studyId":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":594},{"studyId":"mel_dfci_2019","name":"Metastatic Melanoma (DFCI, Nature Medicine 2019)","sampleCount":144},{"studyId":"pancan_pcawg_2020","name":"Pan-cancer analysis of whole genomes (ICGC/TCGA, Nature 2020)","sampleCount":2922}],"genes":["SEPHS1"],"caseSetId":"all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

═ answer (success)
**3 samples** carry one of the SEPHS1 mutations p.Arg371Trp (R371W), p.Arg371Gln (R371Q) or p.Arg371Gly (R371G). I counted samples, using a set of non-overlapping studies so that no sample is counted twice.

| Study | Variant | Samples |
|---|---|---|
| Colorectal Adenocarcinoma (TCGA, PanCancer Atlas), `coadread_tcga_pan_can_atlas_2018` | R371Q | 1 |
| Metastatic Melanoma (DFCI, Nature Medicine 2019), `mel_dfci_2019` | R371W | 1 |
| Pan-cancer analysis of whole genomes (ICGC/TCGA, Nature 2020), `pancan_pcawg_2020` | R371Q | 1 |

- **R371G:** no samples carry it in any study.
- **Total across all studies:** counting every study in the database gives 11 sample entries (R371Q in 9 and R371W in 2). That figure is inflated because many studies share patients. For example, several TCGA colorectal studies and the GDC copies of TCGA and CPTAC data repeat the same tumors. Use 3 as the deduplicated count.
- **Study choice:** you didn't name a study, so I searched the whole database. If you meant a particular cohort, tell me and I'll re-count within it.

[View SEPHS1 R371 mutations in the Mutations tab](https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018%2Cmel_dfci_2019%2Cpancan_pcawg_2020&gene_list=SEPHS1%3A+MUT+%3D+R371W+MUT+%3D+R371Q+MUT+%3D+R371G&case_set_id=all)