Exome Sequencing Identifies Variants in <i>MLH1</i> and <i>ERBB2</i> as Potential Cancer‐Predisposing Factors in Familial Early‐Onset Colorectal Cancer

Colorectal cancer (CRC) has raised considerable health concerns worldwide, with increasing incidence rates, specifically among younger populations. Despite remarkable progress in diagnosing and treating various diseases, the genetic basis of CRC remains only partially understood. This paper aims to examine novel genetic variants associated with CRC in Iranian patients. We performed whole-exome sequencing (WES) in two Iranian families with a history of early-onset CRC. Candidate variants were validated by Sanger sequencing and assessed for segregation. Pathogenicity was evaluated through comprehensive in silico analysis and the application of ACMG/AMP guidelines. Analysis revealed two clinically significant variants. In Family 1, we identified a heterozygous stop-gain variant in MLH1 (c.1043T>A, p.Leu348), a known pathogenic mutation consistent with Lynch syndrome. In Family 2, we discovered a previously undocumented heterozygous missense variant in ERBB2 (c.2268G>T, p.Arg756Ser). Through a detailed ACMG assessment, this ERBB2 variant was classified as Likely Pathogenic based on its location in a critical tyrosine kinase domain, absence from population databases, and concordant deleterious in silico predictions. WES offers a deeper understanding of CRC genetics, suggesting potential biomarkers with promising applications for early diagnosis and targeted treatments, eventually improving patient-related outcomes. The results of this study underscore the significant contribution of genetic screening to the well-being of high-risk families and offer valuable insights for targeted therapeutic approaches.