Tumor analysis identifies Israeli founder pathogenic variation carriers

The Israeli population harbors 53 known founder pathogenic variants in 12 genes found in different ethnicities that increase cancer risk. The current diagnostic yield of founder pathogenic variant testing in Israeli patients with cancer is 2%. In Israeli patients with cancer, somatic mutational profiling is routinely performed to detect mutations in oncogenes and tumor suppressor genes. To better understand the utility of repurposing somatic mutation testing to identify carriers of the known Israeli founder pathogenic variants, we examined to what extent Israeli founder pathogenic variants are found in tumors. By comparing United States ( n = 674,849) and Israeli cohorts ( n = 2769) of tumors tested for somatic mutations, we found that 1 vs. 6% of samples, respectively, harbor an Israeli founder mutation. We tested 69 patients with founder pathogenic variants in their tumor and found a 99% concordance between somatic and germline results. These findings suggest that detection of a founder pathogenic variant in the tumor of a patient from the corresponding founder ethnic group is highly predictive of carrier status. This may warrant cascade screening of at-risk relatives following confirmation of a germline variant in the case index, whenever possible.