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

Rinat Bernstein-Molho, Eitan Friedman, Inbal Kedar, Yael Laitman, Tanir M. Allweis, Einav Nili Gal-Yam, Hagit Baris Feldman, Albert Grinshpun, Naama Halpern, Shulamit Hartmajer, Luna Kadouri, Lior H. Katz, Bella Kaufman, Ido Laish, Keren Levanon, Shira Litz Philipsborn, Mark Ludman, Gal Moran, Tamar Peretz, Eyal ReinsteinGili Reznick Levi, Tamar Safra, Shiri Shkedi, Chana Vinkler, Zohar Levy, Yael Goldberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)445-453
Number of pages9
JournalBreast Cancer Research and Treatment
Volume181
Issue number2
DOIs
StatePublished - 1 Jun 2020

Keywords

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

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