Abstract

To date, few studies have examined the extent to which polygenic single-nucleotide variation (SNV) (formerly single-nucleotide polymorphism) scores modify risk for carriers of pathogenic variants (PVs) in breast cancer susceptibility genes. In previous reports, polygenic risk modification was reduced for BRCA1 and BRCA2 PV carriers compared with noncarriers, but limited information is available for carriers of CHEK2, ATM, or PALB2 PVs.To examine an 86-SNV polygenic risk score (PRS) for BRCA1, BRCA2, CHEK2, ATM, and PALB2 PV carriers.A retrospective case-control study using data on 150 962 women tested with a multigene hereditary cancer panel between July 19, 2016, and January 11, 2019, was conducted in a commercial testing laboratory. Participants included women of European ancestry between the ages of 18 and 84 years.Multivariable logistic regression was used to examine the association of the 86-SNV score with invasive breast cancer after adjusting for age, ancestry, and personal and/or family cancer history. Effect sizes, expressed as standardized odds ratios (ORs) with 95% CIs, were assessed for carriers of PVs in each gene as well as for noncarriers.The median age at hereditary cancer testing of the population was 48 years (range, 18-84 years); there were 141?160 noncarriers in addition to carriers of BRCA1 (n?=?2249), BRCA2 (n?=?2638), CHEK2 (n?=?2564), ATM (n?=?1445), and PALB2 (n?=?906) PVs included in the analysis. The 86-SNV score was associated with breast cancer risk in each of the carrier populations (P?

View details for DOI 10.1001/jamanetworkopen.2020.8501

View details for PubMedID 32609350