Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting

Adam S. Gordon, Elisabeth A. Rosenthal, David S. Carrell, Laura M. Amendola, Michael O. Dorschner, Aaron Scrol, Ian B. Stanaway, Shannon DeVange, James D. Ralston, Hana Zouk, Heidi L. Rehm, Eric Larson, David R. Crosslin, Kathy A. Leppig, Gail P. Jarvik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable incidental findings genes. Those with CRC had a 3.8% rate of positive results (pathogenic or likely pathogenic) for a CRC-associated gene variant, despite generally being older at CRC onset (mean 72 years). Those ascertained for polyps had a 0.8% positive rate and those with no CRC/P had a positive rate of 0.2%. Though incidental finding rates unrelated to colon cancer were similar for all groups, our positive rate for cardiovascular findings exceeds disease prevalence, suggesting that variant interpretation challenges or low penetrance in these genes. The rate of HFE c.845G>A (p.Cys282Tyr) homozygotes in the CRC group reinforces a previously reported, but relatively unexplored, association between hemochromatosis and CRC. These results in a general clinical population suggest that current testing strategies could be improved in order to better detect Mendelian CRC-associated conditions. These data also underscore the need for additional functional and familial evidence to clarify the pathogenicity and penetrance of variants deemed pathogenic or likely pathogenic, particularly among the actionable genes associated with cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)526-533
Number of pages8
JournalAmerican journal of human genetics
Issue number3
StatePublished - Sep 5 2019


  • actionable variant
  • cancer risk
  • clinical sequencing
  • colorectal cancer
  • genetic testing
  • incidental finding
  • panel sequencing
  • polyp

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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