Impact of genetic counselling strategy on diagnostic yield and workload for whole genome sequencing-based tumour diagnostics

Whole genome sequencing (WGS) enables comprehensive molecular analysis of tumours and identification of hereditary cancer predisposition. According to the guidelines, directly determining pathogenic germline variants (PGVs) requires pre-test genetic counselling, which is cost-ineffective. Referral for genetic counselling based on tumour variants alone could miss relevant PGVs and/or result in unnecessary referrals. Here we sought to determine the optimal strategy with high PGV yield and a low number-needed-to counsel (NTC). Therefore, we compared the PGV yield and NTC of three simulated strategies, using paired tumour-normal WGS data from 937 metastatic patients. In strategy-1 genetic counselling of all 937 patients prior to the WGS-tumour testing allowed direct PGV analysis using a tumour type-specific gene panel. In strategy-2 and -3, germline testing and referral for post-test genetic counselling is based on tumour variants using adjusted Dutch guidelines (strategy-2) or ESMO-Precision Medicine Working Group recommendations (strategy-3). In strategy-1, clinically relevant PGVs would be detected in 50 patients (NTC=18.7). In strategy-2, 86 patients would have been referred for genetic counselling and 43 would have clinically relevant PGVs (NTC=2). In strategy-3, 94 patients would have been referred for genetic counselling and 32 would have clinically relevant PGVs (NTC=2.9). Hence, in strategy-2 and -3, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant, primarily in BRCA1/2, PALB2, MLH1, and MSH2/6 genes. Both post-tumour test counselling strategies (2 and 3) had significantly lower NTC compared to pre-tumour test counselling (strategy-1). The adjusted Dutch guidelines had the highest PGV yield per NTC since it was also based on clinical criteria. Both post-tumour test counselling strategies could be improved by using a hybrid approach of directly analysing hereditary predisposition with counselling through mainstreaming for BRCA1/2, PALB2, MLH1, and MSH2/6 genes, along with tumour type-specific strategies for other cancer predisposition genes.