Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants

Background: Carriers of pathogenic variants (PVs) in moderate–high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. Methods: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. Results: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. Conclusions: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.