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Simple Summary: The MRN Complex (MRE11-RAD50-NBS1) is responsible for initiating DNA double-strand break repair and activating several downstream proteins. These proteins have been studied for their individual roles in inherited cancers and are included on several genetic testing panels. However, large amounts of genetic data remain a challenge to interpret due to the presences of variants of uncertain significance (VUS) which prevent proper variant classification and hinders clinical decision making. In this article, we will discuss the current role the MRN complex plays in the DNA repair pathway, the variants present in all three MRN complex genes and the MRN complex as a target for anti-cancer treatment. Repair of a DNA double-strand break relies upon a pathway of proteins to identify damage, regulate cell cycle checkpoints, and repair the damage. This process is initiated by a sensor protein complex, the MRN complex, comprised of three proteins-MRE11, RAD50, and NBS1. After a double-stranded break, the MRN complex recruits and activates ATM, in-turn activating other proteins such as BRCA1/2, ATR, CHEK1/2, PALB2 and RAD51. These proteins have been the focus of many studies for their individual roles in hereditary cancer syndromes and are included on several genetic testing panels. These panels have enabled us to acquire large amounts of genetic data, much of which remains a challenge to interpret due to the presence of variants of uncertain significance (VUS). While the primary aim of clinical testing is to accurately and confidently classify variants in order to inform medical management, the presence of VUSs has led to ambiguity in genetic counseling. Pathogenic variants within MRN complex genes have been implicated in breast, ovarian, prostate, colon cancers and gliomas; however, the hundreds of VUSs within MRE11, RAD50, and NBS1 precludes the application of these data in genetic guidance of carriers. In this review, we discuss the MRN complex's role in DNA double-strand break repair, its interactions with other cancer predisposing genes, the variants that can be found within the three MRN complex genes, and the MRN complex's potential as an anti-cancer therapeutic target. [ABSTRACT FROM AUTHOR]