Germline reflex BRCA1/2 testing following tumor-only comprehensive genomic profiling: why, when, and how

Area of Science:

• Oncology
• Genetics
• Bioinformatics

Background:

• Comprehensive genomic profiling (CGP) is increasingly used in oncology.
• Most CGP currently lacks matched normal controls, complicating germline variant identification.
• Accurate germline pathogenic/likely pathogenic variant (gP/LPV) detection is crucial for patient management and hereditary cancer risk assessment.

Purpose of the Study:

• To develop a strategy for refining germline variant calls from tumor-only CGP.
• To reduce unnecessary germline reflex testing while improving the identification of likely gP/LPV carriers.
• To propose an algorithm for decision-making regarding germline reflex testing for BRCA1/2 variants.

Main Methods:

• Review and adaptation of existing guidelines for gP/LPV identification in BRCA1/2 genes using tumor-only CGP data.
• Development of a decision-making algorithm for germline reflex testing.
• Evaluation of the algorithm's utility in a clinical or simulated setting (details not provided in abstract).

Main Results:

• Guidelines exist for identifying gP/LPVs in BRCA1/2 from tumor-only CGP.
• A strategy is needed to differentiate somatic from germline variants.
• An algorithm is proposed to aid in the decision for germline reflex testing.

Conclusions:

• Tumor-only CGP necessitates robust methods for germline variant interpretation.
• The proposed algorithm aims to optimize the use of germline reflex testing for BRCA1/2 variants.
• Effective strategies can improve the clinical utility of CGP by accurately identifying hereditary cancer predisposition in patients.