BRA-STRAP, Brca Refined Analysis of Sequence Tests: Risk and Penetrance

BRA-STRAP was launched in 2015 to address a significant need to move from single gene testing in clinical genetics services to evidence-based gene panel tests for breast cancer susceptibility.

Since 1997, genetic testing of the BRCA1 and BRCA2 genes had been offered to selected women attending clinical genetics services throughout Australia. For the vast majority of women (~80%) these tests were uninformative (ie negative). Continued research had identified additional breast cancer susceptibility genes and commercial and direct-to-the-public diagnostic testing facilities were including a larger number of genes in gene panel tests made possible via new, massively parallel sequencing technology. These tests posed considerable challenges to clinical genetics services as very little was known about the cancer risks associated with any of the observed genetic variation.

The community urgently needed the evidence from which to translate information about these new and putative breast cancer genes into clinical genetics services and to transition to routinely applying gene panel tests.

BRA-STRAP conducted a large nation-wide study of women at high-risk of breast cancer who had tested negative for pathogenic variants in BRCA1 and BRCA2. BRA-STRAP designed a 24 gene panel test that included ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, FANCM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, STK11 and TP53. This work brought together data representing 30,000 Australian women of all ages across the cancer risk spectrum, affected and unaffected with breast cancer, and their families. Contributing to BRA-STRAP are i) large research cohorts of aging populations and of women above population risk, and ii) the clinical genetics community and women found negative for BRCA1 and BRCA2 mutations following testing in an Australian Familial Cancer Centre over the last 2 decades.

The data enabled Australian population-specific estimates of penetrance and prevalence to be made for several new breast cancer genes that now support the best practice guidelines for genetic testing and risk management for PALB2, ATM and CHEK2 on eviQ (Cancer Treatments Online https://www.eviq.org.au). Pooling with other similar international studies will support further refinement of cancer risk estimates for other genes.