Genetic testing for hereditary breast and ovarian cancer using the GC-HBOC TruRisk® gene panel
20 September 2018 (online)
In the majority of familial BC/OC cases no pathogenic BRCA1/BRCA2 germline mutations can be identified. Therefore the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multi-gene panel (TruRisk®), enabling genetic testing beyond BRCA1/2. It comprises 10 diagnostic „core genes“ and 24 candidate risk genes, currently validated concerning their clinical relevance. The TruRisk panel has been used at the Center for Familial Breast and Ovarian Cancer at the University Hospital Duesseldorf since October 2015. An updated panel version is currently implemented in our laboratory. Included in this evaluation are index patient results up to February 2018.
NGS libraries from blood DNA samples were generated using the SureSelect QXT technology (Agilent), based on enzymatic DNA fragmentation followed by hybridization-mediated panel gene enrichment.
Until February 2018, 1147 TruRisk index analyzes have been evaluated. Pathogenic mutations in BRCA1/2 were identified in 9.9% (114/1147) of patients (class 4/5 according to IARC). In further 4.9% (56/1147) pathogenic mutations were detected in the other core panel genes. Variants of unclear clinical significance (class 3) were detected in 4.0% of patients in BRCA1/2 (46/1147) and 16.4% (188/1147) in the other core genes. In 3.7% (42/1147) of cases, potentially inactivating variants were detected in candidate risk panel genes.
Our TruRisk panel results confirm the low mutation frequencies in non BRCA1/2 core genes while detecting many variants of unclear relevance (VUS). This high VUS-prevalence underscores the need for further gene and variant characterization to finally reclassify them in benign variants or pathogenic mutations.