Co-occurrence of pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome

Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasias associated to germline mismatchrepair gene alterations. We explored whether other pathogenic variants for hereditary cancer genes are present in LS patients and mitght be considered as multilocusinherited-neoplasia-allele-syndrome (MINAS). A cohort of 84 probands with LS diagnosed by Sanger sequencing were reanalyzed using a 94 hereditary cancer genepanel by next-generation sequencing. We found seven families (8.3%) with two germline deleterious variants in dominant cancer-predisposing genes: MLH1/BRCA2/NBN, MLH1/BRCA1, MLH1/FANCA, MSH2/ATM, MSH2/FH, MSH6/FANCI and MSH6/NF1. Interestingly, only one out of these seven families showed a clinical phenotype associated with the new pathogenic variants. The family with pathogenic variants at MLH1/BRCA2/NBN genes showed high incidence of tumors associated to Lynch, and breast and ovarian cancer syndromes. Our results show that the prevalence of MINAS among LS cases is relevant. Although, in most of the cases, no clinical manifestations associated to the secondary pathogenic variants were evidenced, further studies are needed to confirm this finding and elucidate its clinical impact. We suggest reanalyzing LS families to identify new pathogenic alleles, at least in families with complex clinical phenotypes.