Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing

open access: Genetics in Medicine : Nature Publishing Group

Purpose:

Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance.

  

Methods:

Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history.

Results:

Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2.

Conclusion:

The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.
 

Word documents

1. Supplementary Table S1 (688 KB)

   
   

2. Supplementary Table S2 (72 KB)

   
   

3. Supplementary Table S3 (158 KB

Affiliations

1. GeneDx, Gaithersburg, Maryland, USA

   • Lisa R. Susswein,
   • Megan L. Marshall,
   • Rachel Nusbaum,
   • Kristen J. Vogel Postula,
   • Scott M. Weissman,
   • Lauren Yackowski,
   • Erica M. Vaccari,
   • Jeffrey Bissonnette,
   • Jessica K. Booker,
   • Federica Gibellini,
   • Patricia D. Murphy,
   • Daniel E. Pineda-Alvarez,
   • Zhixiong Xu,
   • Gabi Richard,
   • Sherri Bale &
   • Kathleen S. Hruska

2. BioReference Laboratories, Elmwood Park, New Jersey, USA

   • M. Laura Cremona,
   • Guido D. Pollevick &
   • Rachel T. Klein

3. Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA

   • Wendy K. Chung