Jan Henkel

Joint analysis of germline genetic data from over 29,000 cases with suspected hereditary breast and ovarian cancer (HBOC) as part of the NASGE initiative

As multigene panel testing is becoming routine in clinical care, there are recommendations at national and international level, as to which genes should be analyzed in the context of a hereditary breast and ovarian cancer (HBOC). However, the individual composition of gene panels offered by testing laboratories vary, resulting in a different variant diagnostic rate. Therefore, we performed a retrospective NGS dataset analysis of suspected HBOC patients who had been tested at different German diagnostic laboratories that are part of the NASGE network. We collected 29,317 HBOC datasets and compared the diagnostic yield applying the most common panel recommendations and an internal HBOC gene panel. Additionally, we analyzed the data concerning other potential tumor risk syndromes (TRS) not caused by pathogenic variants in the core panel genes. At least one pathogenic variant causative for an autosomal-dominant TRS was identified in 4235 datasets, resulting in an overall diagnostic yield of 14.4 %. The diagnostic yield of pathogenic variants varied depending on the applied HBOC panel (between 5 and 26 genes) from 9.0 % to 13.8 % with the internal HBOC panel having a yield of 12.7 %. Notably, in about 1 % of cases, a pathogenic variant outside the established HBOC core genes was identified, indicating the presence of other TRS. These results are consistent with previous observations that a significant proportion of patients with HBOC predisposition were not detected by the guideline-based gene panels and suggest that expanded diagnostics compared to currently recommended multigene panels may identify additional patients at high risk for developing cancer.

Diagnostic yield and clinical relevance of expanded germline genetic testing for nearly 7000 suspected HBOC patients

AbstractHere we report the results of a retrospective germline analysis of 6941 individuals fulfilling the criteria necessary for genetic testing of hereditary breast- and ovarian cancer (HBOC) according to the German S3 or AGO Guidelines. Genetic testing was performed by next-generation sequencing using 123 cancer-associated genes based on the Illumina TruSight® Cancer Sequencing Panel. In 1431 of 6941 cases (20.6%) at least one variant was reported (ACMG/AMP classes 3–5). Of those 56.3% (n = 806) were class 4 or 5 and 43.7% (n = 625) were a class 3 (VUS). We defined a 14 gene HBOC core gene panel and compared this to a national and different internationally recommended gene panels (German Hereditary Breast and Ovarian Cancer Consortium HBOC Consortium, ClinGen expert Panel, Genomics England PanelsApp) in regard of diagnostic yield, revealing a diagnostic range of pathogenic variants (class 4/5) from 7.8 to 11.6% depending on the panel evaluated. With the 14 HBOC core gene panel having a diagnostic yield of pathogenic variants (class 4/5) of 10.8%. Additionally, 66 (1%) pathogenic variants (ACMG/AMP class 4 or 5) were found in genes outside the 14 HBOC core gene set (secondary findings) that would have been missed with the restriction to the analysis of HBOC genes. Furthermore, we evaluated a workflow for a periodic re-evaluation of variants of uncertain clinical significance (VUS) for the improvement of clinical validity of germline genetic testing.