Important knowledge gaps remain: (i) how concurrent alterations spanning multiple loci (e.g., EpCAM, MSH2, PMS2, and APC) jointly shape penetrance, tumor spectrum, and age at onset; (ii) whether point mutations and structural variants interact to produce tissue-specific silencing and phenotype modification; and (iii) to what extent current surveillance guidelines, which are organized on a gene-by-gene basis, adequately capture multi-locus constellations. This evidence concerns the gene PMS2 and neoplasm.