Towards automation of germline variant curation in clinical cancer genetics

Cancer care professionals are confronted with interpreting results from multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches, requiring aggregation of multiple lines of evidence from diverse resources. The burden of evidence for each variant to meet thresholds for pathogenicity or actionability now poses a growing challenge for those seeking to counsel patients and families following germline genetic testing. A computational algorithm that automates, provides uniformity and significantly accelerates this interpretive process is needed. The tool described here, Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein and disease specific information from public sources. We compared expert manually curated variant data from studies on (i) prostate cancer (ii) breast cancer and (iii) ClinVar to assess performance. PathoMAN achieves high concordance (83.1% pathogenic, 75.5% benign) and negligible discordance (0.04% pathogenic, 0.9% benign) when contrasted against expert curation. Some loss of resolution (8.6% pathogenic, 23.64% benign) and gain of resolution (6.6% pathogenic, 1.6% benign) was also observed. We highlight the advantages and weaknesses related to the programmable automation of variant classification. We also propose a new nosology for the five ACMG classes to facilitate more accurate reporting to ClinVar. The proposed refinements will enhance utility of ClinVar to allow further automation in cancer genetics. PathoMAN will reduce the manual workload of domain level experts. It provides a substantial advance in rapid classification of genetic variants by generating robust models using a knowledge-base of diverse genetic data https://pathoman.mskcc.org .