TY - JOUR T1 - Characterisation of protein-truncating and missense variants in <em>PALB2</em> in 15 768 women from Malaysia and Singapore JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2020-107471 SP - jmedgenet-2020-107471 AU - Pei Sze Ng AU - Rick ACM Boonen AU - Eldarina Wijaya AU - Chan Eng Chong AU - Milan Sharma AU - Sabine Knaup AU - Shivaani Mariapun AU - Weang Kee Ho AU - Joanna Lim AU - Sook-Yee Yoon AU - Nur Aishah Mohd Taib AU - Mee Hoong See AU - Jingmei Li AU - Swee Ho Lim AU - Ern Yu Tan AU - Benita Kiat-Tee Tan AU - Su-Ming Tan AU - Veronique Kiat-Mien Tan AU - Rob Martinus van Dam AU - Kartini Rahmat AU - Cheng Har Yip AU - Sara Carvalho AU - Craig Luccarini AU - Caroline Baynes AU - Alison M Dunning AU - Antonis Antoniou AU - Haico van Attikum AU - Douglas F Easton AU - Mikael Hartman AU - Soo Hwang Teo Y1 - 2021/04/01 UR - http://jmg.bmj.com/content/early/2021/04/01/jmedgenet-2020-107471.abstract N2 - Background Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.Methods Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.Results PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p&lt;0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.Conclusion Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.Data are available upon reasonable request. Access to controlled patient data requires the approval of the Data Access Committee. Requests can be submitted to genetics@cancerresearch.my. ER -