Abstract PS7-04: Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective
Authors: Nguyen-Dumont Tu , Dowty James , Tucker Katherine , Kirk Judy , James Paul , Trainer Alison , Winship Ingrid , Pachter Nicholas , Poplawski Nicola , Grist Scott , Park Daniel J , Renault Anne-Laure , Hammet Fleur , Mahmoodi Maryam , Tsimiklis Helen , Steen Jason A , Theys Derrick , Rewse Amanda , Willis Amanda , Morrow April , Speechly Catherine , Harris Rebecca , Riaz Moeen , Sebra Robert , Schadt Eric , Lacaze Paul , McNeil John , Hopper John L , Southey Melissa C 
Published: February 2021

Abstract
BRA-STRAP is an Australia-wide study of breast cancer predisposition that brings together gene-panel data from 30,000 adult Australian women of all ages, across the breast cancer risk spectrum, with and without a diagnosis of breast cancer. The “BRA-STRAP panel” includes 24 genes* that are involved in, or putatively associated with, predisposition to breast and/or ovarian cancer. Despite insufficient evidence for clinical translation for some of these genes, all 24 are commonly included on panel tests for breast cancer predisposition.
We present findings from the population-based case-control sub-study of BRA-STRAP, which involved 1451 women diagnosed with breast cancer and 857 age-matched controls participating in the Australian Breast Cancer Family Registry (ABCFR), and 6101 healthy, elderly Australian women enrolled in the ASPREE study. These analyses focus on rare genetic variants predicted to lead to loss of function and/or classified as pathogenic/likely pathogenic (P/LP) in ClinVar. Odds ratios (ORs) for their associations with breast cancer were estimated by aggregating genetic variants for each gene.
For the women diagnosed with breast cancer, the median age at diagnosis (inter-quartile range, IQR) was 40.0 (14.0) years and the overall frequency of P/LP variant carriers across all genes was 156/1451 (10.8%). The median age (IQR) of the ABCFR and ASPREE controls were 39.4 (14.9) and 73.9 (5.8) years, respectively. The frequencies of P/LP variant carriers were 33/857 (3.9%) and 268/6101 (4.4%) in the ABCFR and ASPREE controls, respectively. We combined both control datasets and, after adjusting for age and other potential confounders, the ORs associated with P/LP variants in BRCA1 and BRCA2 were 4.1 [95% confidence interval (CI): 1.8-10.2] and 2.9 [95% CI: 1.5-6], respectively. We also found that the OR for P/LP variants in ATM was 4.0 [95% CI: 1.5-10.4] and the OR for P/LP variants in PALB2 was 2.2 [95% CI: 0.75-5.7] although this did not reach statistical significance.
These results contribute to international efforts to refine the breast cancer risk estimates for genetic variants identified from population-based screening of unselected women using genes that are included on panel tests and thought to be potentially breast cancer predisposition genes.The case-control-family design of the ABCFR will also allow us to estimate the age specific cumulative risk (penetrance) of these genetic variants, which is important for genetic counselling and the clinical management of carrier families.
*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
Citation Format: Tu Nguyen-Dumont, James Dowty, Katherine Tucker, Judy Kirk, Paul James, Alison Trainer, Ingrid Winship, Nicholas Pachter, Nicola Poplawski, Scott Grist, Daniel J Park, Anne-Laure Renault, Fleur Hammet, Maryam Mahmoodi, Helen Tsimiklis, Jason A Steen, Derrick Theys, Amanda Rewse, Amanda Willis, April Morrow, Catherine Speechly, Rebecca Harris, Moeen Riaz, Robert Sebra, Eric Schadt, Paul Lacaze, John McNeil, John L Hopper, Melissa C Southey. Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-04.