We report a 52 year old Caucasian male with a referring diagnosis of neurofibromatosis type 1 (NF1), due to multiple nerve sheath tumors, who was subsequently found to have a large deletion spanning CDKN2A,the major melanoma susceptibility gene, and including approximately 24 additional genes underlying his strong family history of melanoma and neural system tumors.  Traditional Sanger sequencing initially missed the CDKN2A deletion.  Knowledge regarding the association of melanoma and neural system tumors, though, informed additional testing that permitted the detection of the large deletion and now provides an accurate test for relatives at potential risk for cancer.  A clinical team was assembled and a management strategy developed to address the unusual constellation of tumors exhibited by family members, not all of which, at this time, have been proven to relate to the large familial deletion. (By Dr. Maria J. Baker, http://jmg.bmj.com/content/early/2016/01/21/jmedgenet-2015-103446 )