Functional Common and Rare Germline Variants Cooperate in Familial and Sporadic Cancer Susceptibility.

We investigated a Spanish and Catalan family in which multiple cancer types tracked across three generations, but for which no genetic etiology had been identified. Whole-exome sequencing of germline DNA from multiple affected family members was performed to identify candidate variants to explain this occurrence of familial cancer. We discovered in all cancer-affected family members a single rare heterozygous germline variant (I654V, rs1801201) in , which is located in a transmembrane glycine zipper motif critical for ERBB2-mediated signaling and in complete linkage disequilibrium (' = 1) with a common polymorphism (I655V, rs1136201) previously reported in some populations as associated with cancer risk.