Q (sonnet): Show me cases where PALB2 or ATM have germline mutations ▶ list_guides {} ◀ result {"result":[{"uri":"cbioportal://mutation-frequency-guide","description":"Comprehensive guide for calculating gene mutation frequencies with gene-specific profiling denominators"},{"uri":"cbioportal://clinical-data-guide","description":"Guide for querying clinical data including patient vs sample level considerations"},{"uri":"cbioportal://sample-filtering-guide","description":"Guide for filtering samples and studies in cBioPortal queries"},{"uri":"cbioportal://common-pitfalls","description":"Guide to avoid common mistakes when querying cBioPortal data. If you already know which numbered pitfall applies, fetch just that section via read_guide(\"cbioportal://common-pitfalls#\") (e.g. #16) instead of the full guide"},{"uri":"cbioportal://treatment-guide","description":"Guide for querying treatment/clinical event data including drug agents, timelines, and linking to genomic data"},{"uri":"cbioportal://faq-guide","description":"General cBioPortal FAQ: history, how to cite, data types, reference genome, abbreviations, GISTIC thresholds, API access"},{"uri":"cbioportal://statistical-tests-guide","description":"Statistical test selection guide — decision matrix for choosing Fisher's exact, Wilcoxon, chi-squared, t-test, ANOVA, etc. based on data type and group count"},{"uri":"cbioportal://gene-expression-guide","description":"Gene expression / copy-number / methylation analysis. Covers genetic_alteration_derived, profile_type discovery, and the gene_pair_coexpression view for Spearman correlation between two genes"},{"uri":"cbioportal://external-resources-guide","description":"Guide for finding external linked resources such as imaging, pathology, Minerva, HTAN, or other resource_* table links before declaring data unavailable"},{"uri":"cbioportal://gene-resolution-guide","description":"Guide for resolving ambiguous gene symbols, aliases, gene families, and shorthand such as CD3 before querying expression or alteration data"},{"uri":"cbioportal://study-resolution-guide","description":"Guide for resolving requested studies, avoiding silent substitute cohorts, and redirecting to known external cBioPortal instances when data is not in this deployment"},{"uri":"cbioportal://germline-guide","description":"Guide for querying germline variant data — storage columns, study discovery, query patterns, and somatic vs germline considerations"},{"uri":"cbioportal://study-guide/{study_id}","description":"Dynamic study-specific guide - use get_study_guide(study_id) tool to generate"}]} ▶ read_guide { "uri": "cbioportal://germline-guide" } ◀ result Germline Variant Guide ====================== Overview -------- cBioPortal stores both somatic AND germline variant data. Many cBioPortal features work identically for both variant types. This guide explains how to query germline variants and what to be aware of. How Germline Data is Stored --------------------------- ### mutation_status is free text — always compare case-insensitively Each study loads its own spelling. Germline calls appear as `'Germline'`, `'GERMLINE'` and `'germline'`; somatic calls as `'Somatic'`, `'SOMATIC'` and `'somatic'`; unannotated mutations as `'NA'`, `'.'`, `'Unknown'`, `'UNKNOWN'`, `'__UNKNOWN__'` and others. Matching one spelling silently drops whole studies (`mutation_status = 'Germline'` misses `all_stjude_2013`, `aml_stjude_2024` and `pog570_bcgsc_2020`). - **Germline:** `upper(mutation_status) = 'GERMLINE'` - **Somatic:** `upper(mutation_status) = 'SOMATIC'` — but only when the user asks for somatic-only. Many studies label their somatic calls `'NA'` or `'UNKNOWN'`, so for ordinary mutation questions follow common-pitfalls #3 and exclude only `'UNCALLED'`. - When unsure, list the values first: `SELECT mutation_status, count() FROM genomic_event_derived WHERE cancer_study_identifier = '{study_id}' AND variant_type = 'mutation' GROUP BY mutation_status` ### Where the column lives - `genomic_event_derived.mutation_status` (preferred): mutations, and structural variants (from `sv_status`: `'SOMATIC'`, `'Somatic'`, `'GERMLINE'`) - `mutation_derived.mutationStatus`: the same values for mutations Identifying Studies with Germline Data -------------------------------------- Not all studies include germline data. Always check before querying: ```sql -- Find studies containing germline mutations SELECT cancer_study_identifier, COUNT(*) as germline_count FROM genomic_event_derived WHERE variant_type = 'mutation' AND upper(mutation_status) = 'GERMLINE' GROUP BY cancer_study_identifier ORDER BY germline_count DESC ``` Common Query Patterns --------------------- ### Count germline vs somatic mutations per gene in a study ```sql SELECT hugo_gene_symbol, upper(mutation_status) AS status, COUNT(*) as count FROM genomic_event_derived WHERE cancer_study_identifier = '{study_id}' AND variant_type = 'mutation' AND upper(mutation_status) IN ('GERMLINE', 'SOMATIC') GROUP BY hugo_gene_symbol, status ORDER BY count DESC LIMIT 20 ``` ### Find patients with germline mutations in a specific gene ```sql SELECT DISTINCT patient_unique_id, sample_unique_id, mutation_variant, mutation_type FROM genomic_event_derived WHERE hugo_gene_symbol = '{GENE}' AND upper(mutation_status) = 'GERMLINE' AND cancer_study_identifier = '{study_id}' AND variant_type = 'mutation' ``` ### Germline mutation frequency The numerator is samples with a germline mutation in the gene; the denominator is samples **profiled** for the gene — not samples that happen to have a mutation in it. Take the denominator from mutation-frequency-guide Step 2 (or … (2222 more chars) ▶ clickhouse_run_select_query { "query": "SELECT cancer_study_identifier, hugo_gene_symbol, COUNT(*) as germline_count FROM genomic_event_derived WHERE variant_type = 'mutation' AND upper(mutation_status) = 'GERMLINE' AND hugo_gene_symbol IN ('PALB2', 'ATM') GROUP BY cancer_study_identifier, hugo_gene_symbol ORDER BY germline_count DESC" } ◀ result {"rows":[{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","germline_count":11},{"cancer_study_identifier":"prad_su2c_2019","hugo_gene_symbol":"ATM","germline_count":8},{"cancer_study_identifier":"pog570_bcgsc_2020","hugo_gene_symbol":"ATM","germline_count":6},{"cancer_study_identifier":"kirc_tcga_pub","hugo_gene_symbol":"ATM","germline_count":3},{"cancer_study_identifier":"lung_nci_2022","hugo_gene_symbol":"ATM","germline_count":2},{"cancer_study_identifier":"pog570_bcgsc_2020","hugo_gene_symbol":"PALB2","germline_count":2}]} ▶ clickhouse_run_select_query { "query": "SELECT cancer_study_identifier, hugo_gene_symbol, patient_unique_id, sample_unique_id, mutation_variant, mutation_type, mutation_status FROM genomic_event_derived WHERE variant_type = 'mutation' AND upper(mutation_status) = 'GERMLINE' AND hugo_gene_symbol IN ('PALB2', 'ATM') ORDER BY cancer_study_identifier, hugo_gene_symbol, patient_unique_id", "max_rows": 50 } ◀ result {"rows":[{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-A2-A0T7","sample_unique_id":"brca_tcga_pub_TCGA-A2-A0T7-01","mutation_variant":"R3047*","mutation_type":"Nonsense_Mutation","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-A8-A08L","sample_unique_id":"brca_tcga_pub_TCGA-A8-A08L-01","mutation_variant":"G2023R","mutation_type":"Missense_Mutation","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-AN-A041","sample_unique_id":"brca_tcga_pub_TCGA-AN-A041-01","mutation_variant":"D1815Tfs*13","mutation_type":"Frame_Shift_Del","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-AN-A049","sample_unique_id":"brca_tcga_pub_TCGA-AN-A049-01","mutation_variant":"Q95*","mutation_type":"Nonsense_Mutation","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-AN-A0XL","sample_unique_id":"brca_tcga_pub_TCGA-AN-A0XL-01","mutation_variant":"X166_splice","mutation_type":"Splice_Site","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-B6-A0RV","sample_unique_id":"brca_tcga_pub_TCGA-B6-A0RV-01","mutation_variant":"X2032_splice","mutation_type":"Splice_Site","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-B6-A0WY","sample_unique_id":"brca_tcga_pub_TCGA-B6-A0WY-01","mutation_variant":"R2547_S2549del","mutation_type":"In_Frame_Del","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-BH-A0DD","sample_unique_id":"brca_tcga_pub_TCGA-BH-A0DD-01","mutation_variant":"R2912G","mutation_type":"Missense_Mutation","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-C8-A12X","sample_unique_id":"brca_tcga_pub_TCGA-C8-A12X-01","mutation_variant":"N1650S","mutation_type":"Missense_Mutation","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-D8-A13Z","sample_unique_id":"brca_tcga_pub_TCGA-D8-A13Z-01","mutation_variant":"X2544_splice","mutation_type":"Splice_Site","mutation_status":"Germline"},{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"brca_tcga_pub_TCGA-E2-A154","sample_unique_id":"brca_tcga_pub_TCGA-E2-A154-01","mutation_variant":"G2023R","mutation_type":"Missense_Mutation","mutation_status":"Germline"},{"cancer_study_identifier":"kirc_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"kirc_tcga_pub_TCG … (5376 more chars) ▶ resolve_and_route { "studyIds": [ "brca_tcga_pub", "kirc_tcga_pub", "lung_nci_2022", "pog570_bcgsc_2020", "prad_su2c_2019" ] } ◀ result {"success":true,"message":"Found 5 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":5,"studiesWithMetadata":[{"studyId":"brca_tcga_pub","name":"Breast Invasive Carcinoma (TCGA, Nature 2012)","sampleCount":825,"studyViewUrl":"https://www.cbioportal.org/study?id=brca_tcga_pub","metadata":{"clinicalAttributeIds":["AGE","CANCER_TYPE","CANCER_TYPE_DETAILED","CN_CLUSTER","CONVERTED_STAGE","ER_STATUS","FRACTION_GENOME_ALTERED","HER2_STATUS","INTEGRATED_CLUSTERS_NO_EXP","INTEGRATED_CLUSTERS_UNSUP_EXP","INTEGRATED_CLUSTERS_WITH_PAM50","METASTASIS","METASTASIS_CODED","METHYLATION_CLUSTER","MIRNA_CLUSTER","MUTATION_COUNT","NODES","NODE_CODED","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","PAM50_SUBTYPE","PR_STATUS","RPPA_CLUSTER","SAMPLE_COUNT","SAMPLE_TYPE","SEX","SIGCLUST_INTRINSIC_MRNA","SIGCLUST_UNSUPERVISED_MRNA","SOMATIC_STATUS","SURVIVAL_DATA_FORM","TMB_NONSYNONYMOUS","TUMOR_STAGE","TUMOR_T1_CODED"],"molecularProfileIds":["brca_tcga_pub_gistic","brca_tcga_pub_linear_CNA","brca_tcga_pub_methylation_hm27","brca_tcga_pub_mirna","brca_tcga_pub_mirna_median_Zscores","brca_tcga_pub_mrna","brca_tcga_pub_mrna_median_Zscores","brca_tcga_pub_mrna_median_all_sample_Zscores","brca_tcga_pub_mrna_merged_median_Zscores","brca_tcga_pub_mutations","brca_tcga_pub_rppa","brca_tcga_pub_rppa_Zscores"],"heatmapProfileIds":["brca_tcga_pub_methylation_hm27","brca_tcga_pub_mrna_median_Zscores","brca_tcga_pub_mrna_median_all_sample_Zscores","brca_tcga_pub_mrna_merged_median_Zscores","brca_tcga_pub_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","dna_methylation"]}},{"studyId":"kirc_tcga_pub","name":"Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)","sampleCount":446,"studyViewUrl":"https://www.cbioportal.org/study?id=kirc_tcga_pub","metadata":{"clinicalAttributeIds":["CANCER_TYPE","CANCER_TYPE_DETAILED","FRACTION_GENOME_ALTERED","MUTATION_COUNT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","SAMPLE_COUNT","SAMPLE_TYPE","SOMATIC_STATUS","TMB_NONSYNONYMOUS"],"molecularProfileIds":["kirc_tcga_pub_gistic","kirc_tcga_pub_linear_CNA","kirc_tcga_pub_methylation_hm27","kirc_tcga_pub_mirna","kirc_tcga_pub_mirna_median_Zscores","kirc_tcga_pub_mrna","kirc_tcga_pub_mrna_median_Zscores","kirc_tcga_pub_mrna_median_all_sample_Zscores","kirc_tcga_pub_mrna_merged_median_Zscores","kirc_tcga_pub_mutations","kirc_tcga_pub_rna_seq_v2_mrna","kirc_tcga_pub_rna_seq_v2_mrna_median_Zscores","kirc_tcga_pub_rna_seq_v2_mrna_median_all_sample_Zscores","kirc_tcga_pub_rppa","kirc_tcga_pub_rppa_Zscores","kirc_tcga_pub_structural_variants"],"heatmapProfileIds":["kirc_tcga_pub_methylation_hm27","kirc_tcga_pub_mirna_median_Zscores","kirc_tcga_pub_mrna_median_Zscores","kirc_tcga_pub_mrna_median_all_sample_Zscores","kirc_tcga_pub_mrna_merged_median_Zscores","kirc_tcga_pub_rn … (3930 more chars) ▶ navigate_to_results_view { "studyIds": [ "brca_tcga_pub", "kirc_tcga_pub", "lung_nci_2022", "pog570_bcgsc_2020", "prad_su2c_2019" ], "genes": [ "PALB2", "ATM" ], "tab": "mutations" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pub%2Ckirc_tcga_pub%2Clung_nci_2022%2Cpog570_bcgsc_2020%2Cprad_su2c_2019&gene_list=PALB2%0AATM&case_set_id=all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pub%2Ckirc_tcga_pub%2Clung_nci_2022%2Cpog570_bcgsc_2020%2Cprad_su2c_2019&gene_list=PALB2%0AATM&case_set_id=all","data":{"studyIds":["brca_tcga_pub","kirc_tcga_pub","lung_nci_2022","pog570_bcgsc_2020","prad_su2c_2019"],"studies":[{"studyId":"brca_tcga_pub","name":"Breast Invasive Carcinoma (TCGA, Nature 2012)","sampleCount":825},{"studyId":"kirc_tcga_pub","name":"Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)","sampleCount":446},{"studyId":"lung_nci_2022","name":"Lung Cancer in Never Smokers (NCI, Nature Genetics 2021)","sampleCount":232},{"studyId":"pog570_bcgsc_2020","name":"Pan-cancer Analysis of Advanced and Metastatic Tumors (BCGSC, Nature Cancer 2020)","sampleCount":570},{"studyId":"prad_su2c_2019","name":"Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team, PNAS 2019)","sampleCount":444}],"genes":["PALB2","ATM"],"caseSetId":"all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}} ═ answer (success) ## Germline PALB2/ATM Mutations Across Studies Querying `genomic_event_derived` for `mutation_status = 'GERMLINE'` (case-insensitive) turned up **32 cases** across 5 studies. Note: this reflects only studies in this database that annotate/retain germline calls — most cBioPortal studies filter these out. ### Summary by study and gene | Study | Gene | Germline cases | |---|---|---| | Breast Invasive Carcinoma (TCGA, Nature 2012) | ATM | 11 | | Metastatic Prostate Adenocarcinoma (SU2C/PCF, PNAS 2019) | ATM | 8 | | Pan-cancer Advanced/Metastatic Tumors (BCGSC, 2020) | ATM | 6 | | Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) | ATM | 3 | | Lung Cancer in Never Smokers (NCI, 2022) | ATM | 2 | | Pan-cancer Advanced/Metastatic Tumors (BCGSC, 2020) | PALB2 | 2 | **Total: 30 ATM germline cases, 2 PALB2 germline cases (32 cases, 32 unique patients)** ### Selected variant detail - **ATM** — truncating variants (nonsense, frameshift, splice-site) predominate: e.g., R3047*, Q95*, D1815Tfs*13, X2032_splice, K2589Nfs*17, W2638*; missense variants also observed (G2023R appears twice independently in `brca_tcga_pub`, E2052K, V2716A, T1743I, N1650S, R2912G). - **PALB2** (pog570_bcgsc_2020 only) — D595Mfs*4 (frameshift deletion) and a splice-site variant. No PALB2 germline cases were found in BRCA, KIRC, lung, or prostate studies in this database — only in the pan-cancer metastatic cohort (pog570_bcgsc_2020). ⚠️ Note: `mutation_status` annotation is inconsistent across cohorts; many studies label all variants `'NA'`/`'UNKNOWN'` rather than distinguishing germline vs. somatic, so absence of germline hits elsewhere does not necessarily mean no germline PALB2/ATM variants exist in those cohorts — it may reflect lack of annotation or germline calling. ### Explore interactively [View PALB2/ATM Mutations Across These 5 Studies](https://www.cbioportal.org/results/mutations?cancer_study_list=brca_tcga_pub%2Ckirc_tcga_pub%2Clung_nci_2022%2Cpog570_bcgsc_2020%2Cprad_su2c_2019&gene_list=PALB2%0AATM&case_set_id=all) Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes (combines somatic + germline — use the Mutation Status column/filter in the table to isolate germline calls).