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

Susswein LR1, Marshall ML1, Nusbaum R1, Vogel Postula KJ1, Weissman SM1, Yackowski L1, Vaccari EM1, Bissonnette J1, Booker JK1, Cremona ML2,Gibellini F1, Murphy PD1, Pineda-Alvarez DE1, Pollevick GD2, Xu Z1, Richard G1, Bale S1, Klein RT2, Hruska KS1, Chung WK3.

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Abstract

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.Genet Med advance online publication 17 December 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.166.