Two founder variants account for over 90% of pathogenic BRCA alleles in Orkney and Shetland

Abstract

20 For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney 21 and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 22 pathogenic variants is important. Two actionable variants in these genes have reached much higher 23 frequencies than in cosmopolitan UK populations. Here, we report a BRCA2 splice acceptor variant, c.517- 24 2A>G, found in breast and ovarian cancer families from Shetland. We investigated the frequency and 25 origin of this variant in a population-based research cohort of people of Shetland ancestry, VIKING I. The 26 variant segregates with female breast and ovarian cancer in diagnosed cases and is classified as 27 pathogenic. Exome sequence data from 2,108 participants with three or more Shetlandic grandparents in 28 VIKING I was used to estimate the population prevalence of c.517-2A>G in Shetlanders. Nine VIKING I 29 research volunteers carry this variant, on a shared haplotype (carrier frequency 0.4%). This frequency is 30 ~130-fold higher than in UK Biobank, where the small group of carriers has a different haplotype. Records 31 of birth, marriage and death indicate genealogical linkage of VIKING I carriers to a founder from the Isle of 32 Whalsay, Shetland, similar to our observations for the BRCA1 founder variant from Westray, Orkney. In 33 total, 93.5% of pathogenic BRCA variant carriers in Northern Isles exomes are accounted for by these two 34 drifted variants. We thus provide the scientific evidence of an opportunity for screening people of 35 Orcadian and Shetlandic origins for each drifted pathogenic variant, particularly women with Westray or 36 Whalsay ancestry. 37 38 Keywords 39 Breast cancer, BRCA2, rare variants, isolate population 2 medRxiv preprint doi: https://doi.org/10.1101/2024.04.03.24305239; this version posted April 6, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 40