Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling

Background The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice. Methods Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne ® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes ( n = 6), or no archived germline DNA samples ( n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan). Results A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 ( n = 2), BRIP1 ( n = 1), BAP1 ( n = 1), PMS2 ( n = 1), MSH2 ( n = 1), and SDHB ( n = 1) remained and six variants (85.7%) were confirmed to be of germline origin. Conclusion Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.