Francesca Duraturo

Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual’s risk of developing cancer.