genomics-pipeline

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:1.4.1

CPSR binary is at /usr/local/bin/cpsr inside this image. Requires a separate data bundle (~21GB).

Prerequisites

Download and extract the PCGR/CPSR data bundle:

mkdir -p ${GENOME_DIR}/pcgr_data
cd ${GENOME_DIR}/pcgr_data
wget -c http://insilico.hpc.uio.no/pcgr/pcgr.databundle.grch38.20220203.tgz
tar xzf pcgr.databundle.grch38.20220203.tgz

This creates a data/ directory with VEP cache, ClinVar, CancerMine, UniProt, and other databases.

Command

docker run --rm \
  --cpus 4 --memory 8g \
  -v ${GENOME_DIR}:/genome \
  sigven/pcgr:1.4.1 \
  cpsr \
    --input_vcf /genome/${SAMPLE}/vcf/${SAMPLE}.vcf.gz \
    --pcgr_dir /genome/pcgr_data \
    --output_dir /genome/${SAMPLE}/cpsr \
    --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 21GB data bundle only needs to be downloaded once — shared across all samples.
• Data bundle staleness: The default bundle (grch38.20220203) dates from February 2022. ClinVar, CancerMine, and UniProt annotations inside the bundle are frozen at that date. Check the PCGR releases page periodically for updated bundles — newer bundles include more recent ClinVar classifications and gene-disease annotations.
• 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 data bundle is used by PCGR for somatic analysis (not relevant for germline WGS).

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