Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance

• DOI: 10.1016/j.ejmg.2022.104468
• Publication Date: 2022-03-01T16:56:19Z
• Authors: Verónica Castillo...; Laura Rosado-Jiménez; María Desamparado...; Miguel Marín-Vera; José Antonio Mací...; Rosario García-He...; Marta Zafra-Poves; Pilar Sánchez-Hen...; María Ángeles Mor...; Encarnación Cueva...; María Arnaldos-Ca...; Francisco Ayala d...; José Luis Alonso-...; José Antonio Nogu...; Francisco Ruiz-Es...
• Keywords: BRCA2 Protein; Ovarian Neoplasms; Multigene panel testing; HBOC; BRCA1 Protein; Genes, BRCA2; Breast Neoplasms; Prioritization algorithm; 3. Good health; Clinical actionability; 03 medical and health sciences; 0302 clinical medicine; Humans; Female; Genetic Predisposition to Disease; Genetic Testing; Molecular Biology; Algorithms

BRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed.an analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master™ Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23.A total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing.The implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies.