In particular among these four cases, one teenage female aged 17, carrying a PMS2 pathogenic variant and a POLE VUS located in the key exonuclease domain, presented with a duodenal adenocarcinoma with a high TMB (111 mutations/Mb) and with the SBS14 MMR/POLE signature, in favor of the involvement of both variants in carcinogenesis. The gene discussed is PMS2; the disease is duodenal adenocarcinoma.