Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH1, Casadei S2, Jacobson AL1, Lee MK2, Gulsuner S2, Bennett RL2, Miller M3, Hall SA4, Hampel H5, Hisama FM2, Naylor LV2, Goetsch C6, Leppig K2,7, Tait JF1, Scroggins SM1, Turner EH1, Livingston R1, Salipante SJ1, King MC2,8, Walsh T2, Pritchard CC1.

Author information

Abstract

PURPOSE:

Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories.

METHODS:

For 1,462 sequential patients referred for testing by BROCA or ColoSeq multigene panels, genomic DNA was sequenced and variants were interpreted by multiple experts using International Agency for Research on Cancer guidelines and incorporating evolutionary conservation, known and predicted variant consequences, and personal and family cancer history. Diagnostic yield was evaluated for various presenting conditions and family-history profiles.

RESULTS:

Of 1,462 patients, 12% carried damaging mutations in established cancer genes. Diagnostic yield varied by clinical presentation. Actionable results were identified for 13% of breast and colorectal cancer patients and for 4% of cancer-free subjects, based on their family histories of cancer. Incidental findings explaining cancer in neither the patient nor the family were present in 1.7% of subjects. Less than 1% of patients carried VUS in BRCA1 or BRCA2. For all genes combined, initial reports contained VUS for 10.5% of patients, which declined to 7.5% of patients after reclassification based on additional information.

CONCLUSIONS:

Individualized interpretation of gene panels is a complex medical activity. Interpretation by multiple experts in the context of personal and family histories maximizes actionable results and minimizes reports of VUS.Genet Med advance online publication 04 February 2016Genetics in Medicine (2016); doi:10.1038/gim.2015.212.