Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world

Abstract

Background Due to historically low uptake of genetic testing, the mutational spectrum of Asians with Hereditary Breast Cancer (HBC) is not well understood. This study sought to understand the incidence and spectrum of germline mutations in Asian patients with suspected HBC in a clinic setting. Methods 1056 patients with suspected HBC were seen in our Cancer (CA) Genetics Clinic from 2000–2017, of which 460 underwent genetic testing. Results Of 460 probands tested, 93% were female, 61% Chinese, 90% had prior CA, with 19% (77/ 414) having 2 primary CA. Median age at CA-diagnosis was 43y (17–83); 70% had Breast CA (BC) and 25% Ovarian CA (OC). 34% had young-onset BC, 8% bilateral BC, and 4% BC/OC. Majority had family history of BC (53%) or OC (20%). 57% underwent multigene testing (14–49 genes), 34% targeted testing, and 8% predictive testing. 30% were found to have a pathogenic mutation: 80% in BRCA1/2 (8 novel mutations noted). Of 33 non-BRCA1/2 pathogenic mutations detected, 61% were in 11 BC genes while 39% were in non-BC genes suggestive of alternative CA syndromes. Testing beyond BRCA1/2 impacted management for 15.9% (22/138) of carriers, but extensive testing identified variants of uncertain significance (VUS) in up to 44.5% of probands. Restricting multigene panel testing to a guideline-based 20-gene panel including Lynch Syndrome genes was found to be most optimal, detecting 94.6% of mutation carriers while reducing VUS rate to 21.5%. Conclusions Evolution of CA Genetics testing strategy to a multigene approach facilitated detection of pathogenic mutations in non-BRCA1/2 genes and aided management. Guideline-based panel testing is feasible and can be offered in Asians with suspected HBC. © 2019 Ow et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.