A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

Genet Med. 2020 Feb;22(2):407-415. doi: 10.1038/s41436-019-0633-8. Epub 2019 Aug 13.


Purpose: Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include.

Methods: To inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT.

Results: We identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria.

Conclusion: Opportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.

Keywords: cancer predisposition; clinical validity; hereditary cancer; multigene panel; testing criteria.

MeSH terms

  • Adult
  • Aged
  • BRCA1 Protein / genetics
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / genetics
  • Cohort Studies
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing / methods*
  • Germ-Line Mutation / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neoplasms / genetics*
  • Ovarian Neoplasms / genetics


  • BRCA1 Protein
  • BRCA1 protein, human
  • Biomarkers, Tumor