| Autor: |
Hirotsu Y; Genome Analysis Center, Yamanashi Central Hospital, Kofu 400-8506, Japan., Schmidt-Edelkraut U; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Nakagomi H; Department of Breast Surgery, Yamanashi Central Hospital, Kofu 400-8506, Japan., Sakamoto I; Department of Obstetrics and Gynecology, Yamanashi Central Hospital, Kofu 400-8506, Japan., Hartenfeller M; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Narang R; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Soldatos TG; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Kaduthanam S; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Wang X; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Hettich S; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Brock S; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Jackson DB; Molecular Health GmbH, Research Department, 69115 Heidelberg, Germany., Omata M; Genome Analysis Center, Yamanashi Central Hospital, Kofu 400-8506, Japan.; University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. |
| Abstrakt: |
BRCA1/2 variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of BRCA1/2 variants from patients with HBOC-related cancer using MH BRCA, a novel computational technology that combines the ACMG guidelines with expert-curated variant annotations. Evaluation of BRCA1/2 variants ( n = 1040) taken from four HBOC studies showed strong concordance within the pathogenic (98.1%) subset. Comparison of MH BRCA's ACMG classification to ClinVar submitter content from ENIGMA, the international consortium of investigators on the clinical significance of BRCA1/2 variants, the ARUP laboratories, a clinical testing lab of the University of UTAH, and the German Cancer Consortium showed 99.98% concordance (4975 out of 4976 variants) in the pathogenic subset. In our patient cohort, refinement of patients with variants of unknown significance reduced the uncertainty of cancer-predisposing syndromes by 64.7% and identified three cases with potential family risk to HBOC due to a likely pathogenic variant BRCA1 p.V1653L (NM_007294.3:c.4957G > T; rs80357261). To assess whether classification results predict PARP inhibitor efficacy, contextualization with functional impact information on DNA repair activity were performed, using MH Guide. We found a strong correlation between treatment efficacy association and MH BRCA classifications. Importantly, low efficacy to PARP inhibition was predicted in 3.95% of pathogenic variants from four examined HBOC studies and our patient cohort, indicating the clinical relevance of the consolidated variant interpretation. |
