Estimate of the penetrance of BRCA mutation and the COS software for the assessment of BRCA mutation probability

• DOI: 10.1007/s10689-014-9766-8
• Publication Date: 2014-11-05T06:01:47Z
• Authors: Jacopo Berrino; Franco Berrino; Silvia Francisci; Bernard Peissel; Jacopo Azzollini; Valeria Pensotti; Paolo Radice; Patrizia Pasanisi; Siranoush Manoukian
• Keywords: Penetrance; BRCA Mutation; Human genetics

We have designed the user-friendly COS software with the intent to improve estimation of the probability of a family carrying a deleterious BRCA gene mutation. The COS software is similar to the widely-used Bayesian-based BRCAPRO software, but it incorporates improved assumptions on cancer incidence in women with and without a deleterious mutation, takes into account relatives up to the fourth degree and allows researchers to consider an hypothetical third gene or a polygenic model of inheritance. Since breast cancer incidence and penetrance increase over generations, we estimated birth-cohort-specific incidence and penetrance curves. We estimated breast and ovarian cancer penetrance in 384 BRCA1 and 229 BRCA2 mutated families. We tested the COS performance in 436 Italian breast/ovarian cancer families including 79 with BRCA1 and 27 with BRCA2 mutations. The area under receiver operator curve (AUROC) was 84.4 %. The best probability threshold for offering the test was 22.9 %, with sensitivity 80.2 % and specificity 80.3 %. Notwithstanding very different assumptions, COS results were similar to BRCAPRO v6.0.