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



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.


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.


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.


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.

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The authors wish to acknowledge Sofia Naftaly Nathan BSc, Study Coordinator and Levona Lago Krispin from Fugene Genetics for data managing.


The work had no specific funding.

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Correspondence to Yael Goldberg.

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Bernstein-Molho, R., Friedman, E., Kedar, I. et al. Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants. Breast Cancer Res Treat 181, 445–453 (2020). https://doi.org/10.1007/s10549-020-05633-2

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  • Multi-gene panel testing
  • Low-penetrance variants
  • Recurrent mutations
  • Clinical utility
  • Cancer predisposition
  • Inherited cancer syndromes