Comprehensive Sequencing of PALB2 in Patients With Breast Cancer Suggests PALB2 Mutations Explain a Subset of Hereditary Breast Cancer

BACKGROUNDThis study sought to determine the prevalence of PALB2 mutations in a cohort referred for diagnostic testing for hereditary breast cancer. METHODSSanger sequencing was used to analyze the entire coding region and flanking introns of PALB2 in anonymized DNA samples from 1479 patients. Samples were stratified into a high-risk group, 955 samples from individuals predicted to have a high probability of carrying a mutation in BRCA1 or BRCA2 based on their personal and family history, and a lower-risk group consisting of 524 samples from patients with breast cancer, but fewer risk factors for being a BRCA1 or BRCA2 mutation carrier. All patients were known to be negative for deleterious sequence mutations and large rearrangements in BRCA1 and BRCA2. RESULTSWe identified 12 disease-associated PALB2 mutations among the 1479 patients (0.8%). The PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice-site mutation. The mutation prevalence for the high-risk population was 1.05% (95% CI=0.5-1.92), whereas that for the lower-risk population was 0.38% (95% CI=0.05-1.37). We identified 59 PALB2 variants of uncertain significance (VUS) among 57 of the 1479 patients (3.9%). CONCLUSIONSThese results suggest that PALB2 mutations occur at a frequency of approximate to 1% in patients with hereditary breast cancer. Cancer 2014;120:963-967. (c) 2013 American Cancer Society. Mutations in PALB2 (partner and localizer of BRCA2) were identified in approximate to 1% of samples from patients with breast cancer who were negative for BRCA1/2 deleterious mutations in the largest cohort to date. This prevalence rate is similar to CHEK2 and ATM mutation rates and suggests that PALB2 mutations explain a subset of patients with familial breast cancer.