Diagnostic yield and clinical relevance of expanded germline genetic testing for hereditary breast- and ovarian cancer patients

As a first step, we report the results of a retrospective germline analysis of nearly 7,000 individuals suspicious of hereditary breast- and ovarian cancer (HBOC) according to the German AGO Guidelines carried out in one of the contributing NASGE (Nationale Allianze für Seltene Genetische Erkrankungen) center. Genetic testing was performed by next-generation sequencing using 123 cancer-associated genes based on the Illumina TruSight®​ Cancer Sequencing Panel. In about 20% of cases at least one variant was reported (ACMG/AMP classes 3-5). Of those 56.3% were a class 4/5. We defined a virtual 14 gene HBOC core gene panel and compared this to one national and different internationally recommended gene panels (German HBOC Consortium, ClinGen expert Panel, Genomics England PanelsApp). Diagnostic yield of pathogenic variants (class 4/5) varied from 7.8% to 11.6% depending on the panel evaluated, with the 14 gene Panel having a yield of 10.8%. Furthermore, we evaluated a workflow for a periodic re-evaluation of variants of uncertain clinical significance (VUS / class 3), reclassifying app. 50% of all VUS into either benign or pathogenic. We also show data concerning the differential diagnosis of hereditary cancer syndromes not caused by pathogenic variants in the core panel genes as 123 cancer-associated genes had been analysed.

As a next step, we incorporated app. 30,000 data sets analysed across different German diagnostic laboratories, which are part of the NASGE network. The NASGE aims to bundle competence in the diagnosis and care of people with rare genetic diseases and thereby improve the quality of care.

Interessenskonflikt

Ich erkläre als korrespondierender Autor, dass meine Koautoren mir mitgeteilt haben, dass sie während der letzten 3 Jahre keine wirtschaftlichen oder persönlichen Verbindungen im oben genannten Sinne hatten. Auch ich selbst hatte keine derartigen Verbindungen in den letzten 3 Jahren.

Publication History

Article published online:
15 June 2023