Hereditary Cancer Genomics: Current Practice, Translational Challenges, and Future Priorities

The expanding scope and sensitivity of genomic testing are reshaping hereditary cancer assessment, shifting attention from the detection of genomic variants alone to the more complex task of determining their significance, biological origin, and relevance to clinical management. This review examines the analytical, biological, and clinical factors that shape this process and integrates them within a five-stage translational framework encompassing variant detection, variant interpretation, biological attribution, clinical validity, and utility. Reliable interpretation requires appropriate test and gene selection, recognition of assay limitations and technically challenging variant classes, and evidence-based variant classification. Computational prediction can support variant interpretation when appropriately validated. Polygenic risk models may further refine risk estimation, although their clinical implementation remains limited by validation, calibration, and population-specific performance. Ancestry-related limitations in genomic resources remain relevant to both variant interpretation and risk estimation. Particular attention is given to biological attribution, illustrated by liquid biopsy, where clonal hematopoiesis can confound the origin and clinical interpretation of plasma variants. Genomic findings must ultimately be considered together with phenotype, family history, gene–disease validity, and disease-specific evidence when informing risk assessment, surveillance, prevention, counseling, or treatment. As hereditary cancer testing continues to expand, its value will depend less on the number of findings generated than on how reliably those findings can be translated into meaningful benefit for patients and families.