Our observations of MSI, loss of MSH2 immuno-expression, and LOH of the wild-type allele in the proband’s rectal adenocarcinoma and similar findings in the tumor of his deceased brother were consistent with the MSH2 c.2006G>T variant serving as the predisposing “first hit” in cancer development. The gene discussed is MSH2; the disease is rectum adenocarcinoma.