The role of non-coding variants in hereditary cancer syndromes: mechanistic insights and clinical implications

Hereditary cancer syndromes have often been associated with genetic mutations in both coding and non-coding regions of DNA. Much attention has been placed on coding mutations, but less so on non-coding variants, which are changes in gene regulation, transcription factor binding, and RNA splicing that are frequently missed in standard genetic tests. The goal of this review is to bring forth the importance of these non-coding mutations in contributing to cancer risk by disrupting gene expression, splicing processes, and epigenetic modifications. We reviewed recent developments in whole-genome sequencing and RNA sequencing, which have enabled better identification of these non-coding variants. The major findings underline the important role that non-coding mutations play in hereditary cancers by changing RNA function and gene regulation. The inclusion of non-coding regions in genetic tests improves our ability to diagnose cancer and predict risk more precisely. Moreover, RNA-targeted therapies, for instance, miRNA inhibitors, can potentially be used for improved treatment of cancers. Despite advances in hereditary cancer testing, a substantial proportion of high-risk individuals remain genetically unresolved after conventional coding-region analysis. Increasing evidence suggests that pathogenic non-coding variants - including enhancer mutations, promoter hypermethylation, deep intronic splice-altering variants, and dysregulated non-coding RNAs - may contribute significantly to hereditary cancer susceptibility and explain a subset of unresolved familial cancer syndromes. This review critically examines the molecular mechanisms, clinical implications, current evidence hierarchy, and translational relevance of non-coding variants in hereditary cancer syndromes. Particular emphasis is placed on functional validation strategies, whole-genome and transcriptomic approaches, and emerging RNA-/epigenetic-targeted therapeutic applications. In the future, efforts should focus on integrating multi-omics data and using state-of-the-art tools, such as CRISPR-based functional genomics, to improve diagnostic precision and personalized therapeutic strategies. This review proposes a mechanistic synthesis and translational framework for understanding non-coding variants in hereditary cancer, highlighting underexplored regulatory elements that escape conventional testing pipelines.