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.
Conflict of interest
All authors declare that they have no conflict of interest.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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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
- Multi-gene panel testing
- Low-penetrance variants
- Recurrent mutations
- Clinical utility
- Cancer predisposition
- Inherited cancer syndromes