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Title: Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore
Authors: Shaw, Tarryn
Chan, Sock Hoai
Teo, Jing Xian
Chong, Siao Ting
Li, Shao-Tzu
Courtney, Eliza
Ishak, Diana
Sankar, Haresh
Ang, Zoe Li Ting
Chiang, Jianbang
Loh, Marie
Zhou, Li
Lee, Soo Chin
Yeh, Hui-Yuan
Kolinjivadi, Arun Mouli
Lim, Weng Khong
Ngeow, Joanne
Keywords: Science::Medicine
Issue Date: 2021
Source: Shaw, T., Chan, S. H., Teo, J. X., Chong, S. T., Li, S., Courtney, E., Ishak, D., Sankar, H., Ang, Z. L. T., Chiang, J., Loh, M., Zhou, L., Lee, S. C., Yeh, H., Kolinjivadi, A. M., Lim, W. K. & Ngeow, J. (2021). Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore. International Journal of Cancer, 148(3), 637-645-645.
Journal: International Journal of Cancer 
Abstract: Identification of ancestry-specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442-22_442-13del variant of unknown significance identified among 13 carriers from six Chinese families, all with a significant history of breast and/or ovarian cancer. We further aimed to establish whether this was due to a founder effect and explore its origins. Haplotype analysis, using nine microsatellite markers encompassing 2.5 megabase pairs around the BRCA1 locus, identified a common haploblock specific to the variant carriers, confirming a founder effect. Variant age was estimated to date back 77.9 generations to 69 bc using the Gamma approach. On principal component analysis using single nucleotide polymorphisms merged with 1000 Genomes dataset, variant carriers were observed to overlap predominantly with the southern Han Chinese population. To determine pathogenicity of the variant, we assessed the functional effect on RAD51 foci formation as well as replication fork stability upon induction of DNA damage and observed an impaired DNA repair response associated with the variant. In summary, we identified an ancient Chinese founder mutation dating back 77.9 generations, possibly common among individuals of southern Han Chinese descent. Using evidence from phenotypic/family history studies, segregation analysis and functional characterization, the BRCA1 variant was reclassified from uncertain significance to pathogenic.
ISSN: 0020-7136
DOI: 10.1002/ijc.33241
Rights: ©2020 Union for International Cancer Control. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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