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

• Published in: Breast cancer research and treatment Vol. 181; no. 2; pp. 445 - 453
• Main Authors: Bernstein-Molho, Rinat, Friedman, Eitan, Kedar, Inbal, Laitman, Yael, Allweis, Tanir M., Gal-Yam, Einav Nili, Feldman, Hagit Baris, Grinshpun, Albert, Halpern, Naama, Hartmajer, Shulamit, Kadouri, Luna, Katz, Lior H., Kaufman, Bella, Laish, Ido, Levanon, Keren, Philipsborn, Shira Litz, Ludman, Mark, Moran, Gal, Peretz, Tamar, Reinstein, Eyal, Levi, Gili Reznick, Safra, Tamar, Shkedi, Shiri, Vinkler, Chana, Levy, Zohar, Goldberg, Yael
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-06-2020; Springer; Springer Nature B.V
• Subjects: Breast cancer; Cancer; Cancer research; Colorectal cancer; Colorectal carcinoma; Disease susceptibility; Epidemiology; Genetic aspects; Genomics; Health aspects; Health risk assessment; Medical tests; Medicine; Medicine & Public Health; Oncology; Ovarian cancer; Polyps; Low-penetrance variants; Clinical utility; Cancer predisposition; Recurrent mutations; Inherited cancer syndromes; Multi-gene panel testing
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-020-05633-2

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.