The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit

Objective To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. Design National retrospective audit. Setting The All Wales Medical Genomics Service (AWMGS). Population Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS. Methods Analysis of NGS data from germline and/or tumour testing. Main outcome measures Frequency of BRCA1 and BRCA2 pathogenic variants. Results The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone. Conclusions Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer. Tweetable abstract Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer.

Automated summary

In this study, the overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included, with a 9.2% germline pathogenic variant detection rate among 791 patients. Parallel tumor and germline testing for 169 patients showed an overall pathogenic variant detection rate of 14.8%, with 6.5% having a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% of patients with a pathogenic variant that would have been missed through tumor testing alone.