RT Journal Article SR Electronic T1 Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 481 OP 491 DO 10.1136/jmedgenet-2020-107471 VO 59 IS 5 A1 Ng, Pei Sze A1 Boonen, Rick ACM A1 Wijaya, Eldarina A1 Chong, Chan Eng A1 Sharma, Milan A1 Knaup, Sabine A1 Mariapun, Shivaani A1 Ho, Weang Kee A1 Lim, Joanna A1 Yoon, Sook-Yee A1 Mohd Taib, Nur Aishah A1 See, Mee Hoong A1 Li, Jingmei A1 Lim, Swee Ho A1 Tan, Ern Yu A1 Tan, Benita Kiat-Tee A1 Tan, Su-Ming A1 Tan, Veronique Kiat-Mien A1 van Dam, Rob Martinus A1 Rahmat, Kartini A1 Yip, Cheng Har A1 Carvalho, Sara A1 Luccarini, Craig A1 Baynes, Caroline A1 Dunning, Alison M A1 Antoniou, Antonis A1 van Attikum, Haico A1 Easton, Douglas F A1 Hartman, Mikael A1 Teo, Soo Hwang YR 2022 UL http://jmg.bmj.com/content/59/5/481.abstract AB 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<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.