Penetrance estimates for <i>BRCA1</i>, <i>BRCA2</i> (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?

Abstract

The identification of <i>BRCA1</i>, <i>BRCA2</i> or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. We assessed the penetrance of <i>BRCA1</i>, <i>BRCA2, MLH1</i> and <i>MSH2</i> mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for <i>BRCA1</i>/<i>BRCA2.</i> RESULTS: Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in <i>BRCA1</i> and <i>BRCA2</i> and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for <i>BRCA1</i>, 60% (95% CI 49% to 71%) for <i>BRCA2</i>, 95% (95% CI 76% to 99%) for <i>MLH1%</i> and 61% (95% CI 49% to 76%) for <i>MSH2</i>. There was no evidence for significant penetrance for males in <i>BRCA1</i> or <i>BRCA2</i> families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in <i>BRCA2</i> but not <i>BRCA1.</i> CONCLUSION: We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.