The previously unreported MSH6 in-frame mutation c.3846_3860del predisposes to Lynch syndrome (OMIM #120435), as it has been classified as pathogenic in two Lynch syndrome families in our institution, with evidence that included demonstration of loss of expression restricted to MSH6 in the colorectal tumors of carriers, a pattern also observed in the colon cancer of a relative of this patient who is also carrier of this in-frame MSH6 variant. Here, MSH6 is linked to colonic neoplasm.