Spectrum of double heterozygosity in individuals diagnosed with hereditary breast and ovarian cancer

Clinical spectrum and phenotypic impact of double heterozygosity for HBOC gene pathogenic variants

Drawing on the prospective German HBOC registry (26,983 carriers), this case-control study characterizes the 409 individuals carrying multiple pathogenic variants, including 400 double heterozygotes. Double heterozygosity affects 2.9% of individuals in a subgroup tested for 13 core genes — more frequent than assumed. Gene constellations reshape the phenotype: double BRCA1 + another gene carriers mostly develop triple-negative cancers, and double BRCA1/BRCA2 carriers show greater severity than single heterozygotes. Integrating double heterozygosity into risk assessment could refine personalized surveillance in the multigene testing era.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Highly relevant work in the era of panels and broad sequencing: the more genes tested, the more double heterozygotes identified, and it becomes essential to know how to counsel these families. The message that gene-gene combinations can reshape the phenotype, rather than adding two independent risks, should make us cautious in counseling. One more argument for broad, well-annotated analyses where interpretation takes precedence over a priori gene selection.