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Step 17: Cancer Predisposition Screening with CPSR

What This Does

Screens germline variants against curated cancer predisposition gene panels to identify clinically actionable cancer risk variants. CPSR uses its own panels sourced from Genomics England PanelApp and other curated databases — these are cancer-focused and distinct from the 81-gene ACMG SF v3.2 list (which also includes cardiac and metabolic genes not covered by CPSR).

Why

ClinVar screening (step 6) finds known pathogenic variants, but CPSR applies ACMG/AMP classification criteria to novel or rare variants in cancer predisposition genes — catching variants ClinVar hasn't yet classified.

Tool

  • CPSR (Cancer Predisposition Sequencing Reporter), bundled inside the PCGR image

Docker Image

sigven/pcgr:2.2.5

CPSR binary is at /usr/local/bin/cpsr inside this image. Requires a separate ref data bundle (~5 GB) and a VEP cache.

Prerequisites

1. VEP Cache

PCGR 2.2.5 bundles VEP 113, which requires the release-113 cache. This is different from the release-112 cache used by step 13 — both coexist in the same vep_cache/ directory under different subdirectories (112_GRCh38/ and 113_GRCh38/).

mkdir -p ${GENOME_DIR}/vep_cache
wget -c -P ${GENOME_DIR}/vep_cache https://ftp.ensembl.org/pub/release-113/variation/indexed_vep_cache/homo_sapiens_vep_113_GRCh38.tar.gz
tar xzf ${GENOME_DIR}/vep_cache/homo_sapiens_vep_113_GRCh38.tar.gz -C ${GENOME_DIR}/vep_cache

2. PCGR Ref Data Bundle

PCGR 2.x uses a new, smaller ref data bundle (~5 GB) separate from VEP:

mkdir -p ${GENOME_DIR}/pcgr_data
cd ${GENOME_DIR}/pcgr_data
wget -c https://insilico.hpc.uio.no/pcgr/pcgr_ref_data.20250314.grch38.tgz
tar xzf pcgr_ref_data.20250314.grch38.tgz
mkdir -p 20250314 && mv data/ 20250314/

This creates a 20250314/data/ directory with ClinVar, CancerMine, UniProt, and other databases. VEP cache is now mounted separately.

Command

docker run --rm --user root \
  --cpus 4 --memory 8g \
  -v ${GENOME_DIR}/vep_cache:/mnt/.vep \
  -v ${GENOME_DIR}/pcgr_data/20250314:/mnt/bundle \
  -v ${GENOME_DIR}/${SAMPLE}/vcf:/mnt/inputs \
  -v ${GENOME_DIR}/${SAMPLE}/cpsr:/mnt/outputs \
  sigven/pcgr:2.2.5 \
  cpsr \
    --input_vcf /mnt/inputs/${SAMPLE}.vcf.gz \
    --vep_dir /mnt/.vep \
    --refdata_dir /mnt/bundle \
    --output_dir /mnt/outputs \
    --genome_assembly grch38 \
    --sample_id ${SAMPLE} \
    --panel_id 0 \
    --classify_all \
    --force_overwrite

Panel Options

Panel ID Description
0 Comprehensive cancer superpanel (500+ genes) — recommended
1 Adult-onset hereditary cancer
2 Childhood-onset hereditary cancer
3 Lynch syndrome
4 BRCA1/BRCA2

Output

  • ${SAMPLE}.cpsr.grch38.html — Interactive HTML report with classified variants
  • ${SAMPLE}.cpsr.grch38.snvs_indels.tiers.tsv — Tab-separated variant classifications
  • Variants classified into 5 tiers (Pathogenic → Benign) using ACMG/AMP criteria

Runtime

~30-60 minutes per genome (depends on variant count).

Notes

  • The ref data bundle (~5 GB) and VEP cache only need to be downloaded once — shared across all samples.
  • PCGR 2.x breaking changes: The CLI changed completely from 1.x. The old --pcgr_dir flag (which internally appended /data) is replaced by --refdata_dir and --vep_dir as separate mount points. The single monolithic data bundle is split into a smaller ref data bundle + the standard Ensembl VEP cache. Docker volume mounts changed from a single :/genome to four separate mounts for VEP, bundle, inputs, and outputs.
  • Data bundle freshness: The 20250314 bundle dates from March 2025. Check the PCGR releases page periodically for updated bundles — newer bundles include more recent ClinVar classifications and gene-disease annotations.
  • VEP cache version: PCGR 2.2.5 requires VEP release-113 cache, while step 13 uses release-112. Both coexist in vep_cache/homo_sapiens/ (subdirectories 112_GRCh38/ and 113_GRCh38/). You need both if running both steps.
  • Use --panel_id 0 for the comprehensive cancer superpanel (500+ genes). Note: this is broader than ACMG SF but cancer-focused — it does not replace a full ACMG incidental-findings screen.
  • --classify_all ensures all variants in target genes get ACMG classification, not just known pathogenic.
  • CPSR is complementary to ClinVar screening — ClinVar finds known variants, CPSR classifies novel ones.
  • The same ref data bundle is used by PCGR for somatic analysis (not relevant for germline WGS).