Q (sonnet-5.5): Show me cases where PALB2 or ATM have germline mutations

▶ 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(DISTINCT patient_unique_id) AS patients, COUNT(DISTINCT sample_unique_id) AS samples
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 patients DESC"
}

◀ result
{"rows":[{"cancer_study_identifier":"brca_tcga_pub","hugo_gene_symbol":"ATM","patients":11,"samples":11},{"cancer_study_identifier":"prad_su2c_2019","hugo_gene_symbol":"ATM","patients":7,"samples":8},{"cancer_study_identifier":"pog570_bcgsc_2020","hugo_gene_symbol":"ATM","patients":6,"samples":6},{"cancer_study_identifier":"kirc_tcga_pub","hugo_gene_symbol":"ATM","patients":3,"samples":3},{"cancer_study_identifier":"lung_nci_2022","hugo_gene_symbol":"ATM","patients":2,"samples":2},{"cancer_study_identifier":"pog570_bcgsc_2020","hugo_gene_symbol":"PALB2","patients":2,"samples":2}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT cancer_study_identifier, hugo_gene_symbol, patient_unique_id, sample_unique_id, mutation_variant, mutation_type
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"
}

▶ resolve_and_route
{
 "studyIds": [
  "brca_tcga_pub",
  "prad_su2c_2019",
  "pog570_bcgsc_2020",
  "kirc_tcga_pub",
  "lung_nci_2022"
 ]
}

◀ 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"},{"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"},{"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"},{"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"},{"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"},{"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"},{"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"},{"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"},{"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"},{"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"},{"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"},{"cancer_study_identifier":"kirc_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"kirc_tcga_pub_TCGA-B0-5097","sample_unique_id":"kirc_tcga_pub_TCGA-B0-5097-01","mutation_variant":"S496Ifs*16","mutation_type":"Frame_Shift_Del"},{"cancer_study_identifier":"kirc_tcga_pub","hugo_gene_symbol":"ATM","patient_unique_id":"kirc_tcga_pub_TCGA-BP-4988","sample_unique_id":"kirc_tcga_pub_TCGA-BP-4988-01","mutation_variant":"X9 … (4448 more chars)

◀ 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":"prad_su2c_2019","name":"Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team, PNAS 2019)","sampleCount":444,"studyViewUrl":"https://www.cbioportal.org/study?id=prad_su2c_2019","metadata":{"clinicalAttributeIds":["ABI_ENZA_EXPOSURE_STATUS","AGE_AT_DIAGNOSIS","AGE_AT_PROCUREMENT","AR_CAPTURE_SCORE","AR_POLYA_SCORE","AR_SCORE","CANCER_TYPE","CANCER_TYPE_DETAILED","CAPTURE_ARV7_SRPM","CHEMO_REGIMEN_CATEGORY","ETS_FUSION_DETAILS","ETS_FUSION_SEQ","FRACTION_GENOME_ALTERED","GLEASON_SCORE","MUTATION_COUNT","NEPC_CAPTURE_SCORE","NEPC_POLYA_SCORE","NEPC_SCORE","NEUROENDOCRINE_FEATURES","OFF_ARSI","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_SAMPLE_ID","PATHOLOGY_CLASSIFICATION","POLYA_ARV7_SRPM","PSA","RACE","RAF1_BRAF_STATUS","SAMPLE_COUNT","SEX","SOMATIC_STATUS","TAXANE_EXPOSURE_STATUS","TISSUE_SITE","TISSUE_SOURCE_SITE","TMB_NONSYNONYMOUS","UNIQUE_PAPER_SAMPLES"],"molecularProfileIds":["prad_su2c_2019_gistic","prad_su2c_2019_mrna_seq_fpkm_capture","prad_su2c_2019_mrna_seq_fpkm_capture_Zscores","prad_su2c_2019_mrna_seq_fpkm_capture_all_sample_Zscores","prad_su2c_2019_mrna_seq_fpkm_polya","prad_su2c_2019_mrna_seq_fpkm_polya_Zscores","prad_su2c_2019_mrna_seq_fpkm_poly … (3930 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "brca_tcga_pub",
  "prad_su2c_2019",
  "pog570_bcgsc_2020",
  "kirc_tcga_pub",
  "lung_nci_2022"
 ],
 "genes": [
  "PALB2: MUT = GERMLINE",
  "ATM: MUT = GERMLINE"
 ],
 "tab": "oncoprint"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/oncoprint?cancer_study_list=brca_tcga_pub%2Cprad_su2c_2019%2Cpog570_bcgsc_2020%2Ckirc_tcga_pub%2Clung_nci_2022&gene_list=PALB2%3A+MUT+%3D+GERMLINE%0AATM%3A+MUT+%3D+GERMLINE&case_set_id=all","url":"https://www.cbioportal.org/results/oncoprint?cancer_study_list=brca_tcga_pub%2Cprad_su2c_2019%2Cpog570_bcgsc_2020%2Ckirc_tcga_pub%2Clung_nci_2022&gene_list=PALB2%3A+MUT+%3D+GERMLINE%0AATM%3A+MUT+%3D+GERMLINE&case_set_id=all","data":{"studyIds":["brca_tcga_pub","prad_su2c_2019","pog570_bcgsc_2020","kirc_tcga_pub","lung_nci_2022"],"studies":[{"studyId":"brca_tcga_pub","name":"Breast Invasive Carcinoma (TCGA, Nature 2012)","sampleCount":825},{"studyId":"prad_su2c_2019","name":"Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team, PNAS 2019)","sampleCount":444},{"studyId":"pog570_bcgsc_2020","name":"Pan-cancer Analysis of Advanced and Metastatic Tumors (BCGSC, Nature Cancer 2020)","sampleCount":570},{"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}],"genes":["PALB2","ATM"],"caseSetId":"all","pageDescription":"Visual summary of alterations in queried genes across samples."}}

═ answer (success)
I found 32 germline mutation calls in ATM or PALB2. They come from 30 patients in 5 studies. Germline PALB2 calls appear in only one study.

**Patients with germline mutations, by study and gene**

| Study | Gene | Patients |
|---|---|---|
| [Breast Invasive Carcinoma (TCGA, Nature 2012)](https://www.cbioportal.org/study/summary?id=brca_tcga_pub) | ATM | 11 |
| [Metastatic Prostate Adenocarcinoma (SU2C/PCF, PNAS 2019)](https://www.cbioportal.org/study/summary?id=prad_su2c_2019) | ATM | 7 (8 samples) |
| [Pan-cancer Advanced and Metastatic Tumors (BCGSC, Nature Cancer 2020)](https://www.cbioportal.org/study/summary?id=pog570_bcgsc_2020) | ATM | 6 |
| [Pan-cancer Advanced and Metastatic Tumors (BCGSC, Nature Cancer 2020)](https://www.cbioportal.org/study/summary?id=pog570_bcgsc_2020) | PALB2 | 2 |
| [Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)](https://www.cbioportal.org/study/summary?id=kirc_tcga_pub) | ATM | 3 |
| [Lung Cancer in Never Smokers (NCI, Nat Genet 2021)](https://www.cbioportal.org/study/summary?id=lung_nci_2022) | ATM | 2 |

**Cases and variants**

*PALB2 (pog570_bcgsc_2020)*
- 18154: D595Mfs*4 (frameshift deletion)
- 26850: splice site (no protein change listed)

*ATM, breast (brca_tcga_pub)*
- TCGA-A2-A0T7: R3047* (nonsense)
- TCGA-A8-A08L: G2023R (missense)
- TCGA-AN-A041: D1815Tfs*13 (frameshift)
- TCGA-AN-A049: Q95* (nonsense)
- TCGA-AN-A0XL: X166_splice
- TCGA-B6-A0RV: X2032_splice
- TCGA-B6-A0WY: R2547_S2549del (in-frame deletion)
- TCGA-BH-A0DD: R2912G (missense)
- TCGA-C8-A12X: N1650S (missense)
- TCGA-D8-A13Z: X2544_splice
- TCGA-E2-A154: G2023R (missense)

*ATM, prostate (prad_su2c_2019)*
- 1115082: K2589Nfs*17 (frameshift), present in 2 samples
- 5115194: X2544_splice
- 96115206: L1255*
- 97115005: Q1852* (nonsense)
- 97115131: V1268*
- 97115167: W2638* (nonsense)
- 97115333: E1971Rfs*19 (frameshift)

*ATM, pan-cancer (pog570_bcgsc_2020)*
- 25438: S1905Ifs*25 (frameshift)
- 27216: T1743I (missense)
- 28124: R1907Nfs*22 (frameshift)
- 28638: E2052K (missense)
- 30222: V2716A (missense)
- 31518: V2424G (missense)

*ATM, kidney (kirc_tcga_pub)*
- TCGA-B0-5097: S496Ifs*16 (frameshift)
- TCGA-BP-4988: X974_splice
- TCGA-BP-5009: Q2066Rfs*16 (frameshift)

*ATM, lung (lung_nci_2022)*
- NSLC-0079: W1221* (nonsense)
- NSLC-0101: X974_splice

- **Germline label:** these are calls that a study labels as germline. Other studies may have germline variants that are labeled "unknown" or not reported, so they wouldn't appear here.
- **Pathogenicity:** cBioPortal doesn't store a pathogenicity classification for these variants, so the list includes missense variants that may be of uncertain significance.

[Open the germline PALB2 / ATM OncoPrint across these 5 studies](https://www.cbioportal.org/results/oncoprint?cancer_study_list=brca_tcga_pub%2Cprad_su2c_2019%2Cpog570_bcgsc_2020%2Ckirc_tcga_pub%2Clung_nci_2022&gene_list=PALB2%3A+MUT+%3D+GERMLINE%0AATM%3A+MUT+%3D+GERMLINE&case_set_id=all)