Light and shade of multigene panel testing for hereditary cancer: Examples from the real world

MultiGene Panel Testing (MGPT) allows for simultaneous analysis of multiple cancer-related genes, enabling the identification of pathogenic variants in genes beyond those that would be analyzed based on a specific phenotype. However, a relevant fraction of variants so identified has little or no clinical utility, raising the need for guidance in selecting genes to include in panels and for interpretation of the results.

Taking advantage of seven real paradigmatic cases, we analyze some of the scenarios where MGPT constitutes a meaningful advantage for diagnosis, as well as situations where panel use increases the risk of misinterpretation or complicates result communication and management.

The use of MGPT facilitates prompt diagnosis in carriers of variants in rare genes (such as NTHL1), which would be diagnosed at a later stage if using a step-wise approach, as well as in carriers of bi-allelic variants (for instance in BRCA or MMR genes) leading to atypical phenotypes. Conversely, finding variants in moderate penetrance genes, such as ATM and CHEK2, may complicate interpretation and clinical management. Furthermore, for some of the genes included in MGPT, for instance NBN, the association with cancer risk has been questioned, leading to potentially misleading results.

Taken together, the cases here described provide some examples of the benefits, as well as risks, involved by the use of MGPT, which may increase awareness among users and reinforce the need for establishing clear recommendations on genes to be included and management of the results.