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

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.