Clinical Discovery and Molecular Analysis of Two Novel MSH2 Gene Mutations (p.Ala771Gly and p.Val797Gly) in Saudi Colorectal Cancer Patients: Potential Implications for Tumorigenesis

ABSTRACT Background and Aims Colorectal cancer (CRC) is a serious global health problem, ranking first in men and third in women among all cancers worldwide. The genetic basis for CRC remains unclear in most cases; therefore, the present study aimed to investigate the molecular genetic basis of CRC and correlate it with disease outcomes. Methods Tumor tissues were obtained from 84 Saudi CRC patients, and their disease data and tumor characteristics were recorded. The MutS homolog 2 ( MSH2 ) gene was analyzed for molecular underlying pathogenic variants, and various bioinformatic approaches were utilized to predict the lethality of these variants and their association with cancer pathogenicity. Results A total of 17 variants in four CRC types were identified in 14 patients of whom two were novel missense variations, c.2312 C > G (p.Ala771Gly) and c.2390 T > G (p. Val797Gly). The p.Ala771Gly variant was detected in five individuals (5.95% allelic frequency), while the p.Val797Gly variant was found in three patients (3.57% allelic frequency). Further analysis using the Have (y)Our Protein Explained (HOPE) tool predicted that these variants may deleteriously affect MSH2 protein‐DNA and ATP binding, resulting in functional damage to MSH2, which impairs its functions and protein‐binding affinities. Conclusion This study provides new insights into the genetic basis of CRC and highlights the importance of molecular analysis for detecting novel variants. These novel mutations can be therapeutic targets for novel drugs in precision medicine.