Background Pathogenic mutation in BRCA genes causes high cancer risk. Identifying the mutation carriers plays key roles in preventing BRCA mutation-related cancer. Population screening has demonstrated its power for comprehensive identification of the mutation carriers. However, it is only recommended for the Ashkenazi Jewish population with high prevalence of three founder mutations, but not for non-Ashkenazi Jewish populations as the cost-effectiveness could be too low due to their lower mutation prevalence and lack of founder mutation. Population screening would not benefit the majority of the human population for BRCA mutation-related cancer prevention. Methods We used population BRCA screening in 6000 residents, 1% of the Macau population, an ethnic Chinese population with unique genetic, linguistic and cultural features, and its BRCA mutation has not been analysed before. Results We called BRCA variants, identified 18 carriers with 14 pathogenic mutations and determined the prevalence of 0.29% in the population (95% CI 0.15% to 0.42%). We compared the testing cost between the Ashkenazi Jewish population, the Sephardi Jewish population and the Macau population, and observed only a few fold differences. Conclusion Our study shows that testing cost is not the most important factor in considering population BRCA screening, at least for the populations in the developed countries/regions, regardless of the status of mutation prevalence and founder mutation.
Background Pathogenic variation in BRCA1 and BRCA2 (BRCA) is one of the most frequent genetic predispositions for hereditary breast cancer. The identification of the variant carriers plays an important role in prevention and treatment of cancer. Despite a population size of 1.4 billion and a quarter million annual new breast cancer cases, knowledge regarding the prevalence of BRCA variation in the Chinese population remains elusive. Methods In this study, we used BRCA-targeted sequencing and bio...
Guidelines for variant interpretation incorporate variant hotspots in critical functional domains as evidence for pathogenicity (e.g., PM1 and PP2), but do not use “coldspots,” that is, regions without essential functions that tolerate variation, as evidence a variant is benign. To improve variant classification we evaluated BRCA1 and BRCA2 missense variants reported in ClinVar to identify regions where pathogenic missenses are extremely infrequent, defined as coldspots. We used Bayesian approac...
Interpretation of variants of unknown significance (VUS) in genetic tests is complicated in ethnically diverse populations, given the lack of information regarding the common spectrum of genetic variation in clinically relevant genes. Public availability of data obtained from high-throughput genotyping and/or exome massive parallel sequencing (MPS)-based projects from several thousands of outbred samples might become useful tools to evaluate the pathogenicity of a VUS, based on its frequency in ...
Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Patho...
Importance Detection of disease-associated variants in theBRCA1andBRCA2(BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. Objectives To identify pathogenic and likely pathogenic (P/LP)BRCA1/2variants in an unselected research cohort, and to characterize the features associated with P/LP variants. Design, Setting, and Participants This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (...
#1Shreeya Patel(Lond: University of London)H-Index: 4
#2Rosa Legood(Lond: University of London)H-Index: 28
Last. Ranjit Manchanda(UCL: University College London)H-Index: 21
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BACKGROUND: Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost-effective compared to family-history(FH) based testing in Ashkenazi Jewish(AJ) women. However, only one of the three AJ BRCA1/BRCA2 founder-mutations (185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT)) is found in the Sephardi Jewish(SJ) population (185delAG(c.68_69delAG)) and the overall prevalence of BRCA mutations in the SJ population is accordingly lower (0.7% compared to 2.5% ...
Importance The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at basel...
Last. Timothy A. Yap(ICR: Institute of Cancer Research)H-Index: 36
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J.S. Brown, B. O'Carrigan, and T.A. Yap acknowledge support from the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). Research in The Jackson laboratory is funded by Cancer Research UK (CRUK) program grant number C6/A18796. Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P....
Background null Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including MLH1, MSH2, MSH6 and PMS2 play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spe...
Last. San Ming Wang(UM: University of Macau)H-Index: 28
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BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. Rapidly evolving human BRCA generates oncogenic variants causing high cancer risk. BRCA variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift. Taiwanese population of 23.8 million is an admixture of multiple ethnic origins; Taiwan's subtropical and tropical climate and geographically islandic location provide a unique natural environment. Therefore, Taiwanese population provides a unique ...
