Dual germline BRCA and mismatch-repair mutations: a narrative review.

Abstract

INTRODUCTION Multilocus inherited neoplasia alleles syndrome (MINAS) can pair a germline pathogenic BRCA1/2 variant with a pathogenic mismatch-repair (MMR) variant, but current guidelines manage the two inherited pathways separately. AREAS COVERED We searched PubMed, Embase, the American Society of Clinical Oncology Library, European Society for Medical Oncology OncologyPro, and Society of Gynecologic Oncology library from 2011 to 17 May 2026. It distinguishes a dual germline carrier from single-track, dual-defective, and biomarker-discordant tumors. For mismatch-repair immunohistochemistry (IHC)-deficient but microsatellite-stable results, particularly with isolated MSH6 loss, we propose technical review followed by a validated orthogonal assay when needed. The evidence for poly(ADP-ribose) polymerase inhibitor (PARPi) plus immune checkpoint inhibitor (ICI) therapy is assessed through the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) hypothesis and TOPACIO, MEDIOLA, and DUO-E. EXPERT OPINION Management should combine gene-specific surveillance with tumor-level biomarkers and shared decision-making. Treatment should not be inferred from dual germline status alone, and no phase III trial has predefined dual carriers as a treatment stratum.