Cancer Predisposition Sequencing Reporter (CPSR): a flexible variant report engine for germline screening in cancer

Motivation: While somatic mutagenesis is the driving force of most human cancers, the germline genome is of significant clinical value in several tumor types. Cancer predisposition variants are important for risk management and surveillance, and can also have major implications for treatment strategies since many are in DNA repair genes. Following the incorporation of high-throughput DNA sequencing in cancer clinics and research, there is thus a need to provide clinically oriented sequencing reports for risk-associated germline variants and their potential therapeutic relevance on a per patient basis. Results: We have developed the Cancer Predisposition Sequencing Reporter (CPSR), an open-source computational workflow that provides a structured report of germline variants identified in known cancer predisposition genes. Building upon existing knowledge sources and variant databases relevant for cancer susceptibility, CPSR combines a transparent and cancer-dedicated scoring scheme for variant pathogenicity (American College of Medical Genetics and Genomics, ACMG) with existing variant classifications from ClinVar in order to derive a structured and prioritised list of variant findings. The workflow outputs a comprehensive and interactive HTML report that highlights putative markers of therapeutic, prognostic and diagnostic relevance. Importantly, the set of cancer predisposition genes profiled in the report can be flexibly chosen from nearly 40 virtual gene panels established by scientific experts, enabling a customization of the report for different screening purposes. The report can be configured to also list potential incidental variant findings as recommended by ACMG, as well as the status of low-risk variants from genome-wide association studies in cancer. Availability and Implementation: The software is implemented in Python/R, and is freely available through Docker technology. Documentation, example reports, and installation instructions are accessible via the project GitHub page: https://github.com/sigven/cpsr .