Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model

Genetics in Medicine

(2016)

doi:10.1038/gim.2016.31

Received: 29 October 2015
Accepted: 01 February 2016
Published online: 14 April 2016

Abstract

Purpose:

The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, andATM.

Methods:

The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2,CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods.

Results:

The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry aCHEK2 or ATM mutation, the risks decrease slightly.

Conclusions:

The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).

Genet Med advance online publication 07 April 2016

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