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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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mammographic density is a strong risk factor for breast cancer and is highly variable, but, to date, few studies have examined density in Asian women, particularly those in low and middle-income Asian countries where genetic and lifestyle determinants may be significantly different., Methods: A total of 1,240 women who attended an opportunistic mammogram screening programme were eligible for analysis. Mammographic density was estimated using a fully-automated thresholding method and differences across ethnic groups were examined using linear regression in 205 randomly selected Chinese women, 138 Malay and 199 Indian women., Results: Percent density was significantly higher in Chinese women (28.5%; 95% CI 27.0%, 30.0%) compared to Malay (24.2%; 95% CI 22.5%, 26.0%) and Indian (24.3%; 95% CI 22.8%, 25.7%) women (p<0.001), after adjustment for age, BMI, menopausal status, parity and age at first full term pregnancy. Correspondingly, adjusted nondense area was significantly lower in Chinese (72.2cm2; 95% CI 67.9cm2, 76.5cm2) women compared to Malay (92.1cm2; 95% CI 86.9cm2, 97.2cm2) and Indian (97.7cm2; 95% CI 93.4cm2, 101.9cm2) women (p<0.001), but dense area did not differ across the three ethnic groups., Conclusions: Our study shows that higher percent density and lower nondense area reflect the higher incidence of breast cancer in Chinese compared to Malay and Indian women in Malaysia. Known lifestyle determinants of mammographic density do not fully account for the ethnic variations observed in mammographic density in this Asian cohort.