40 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2,088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.
The study team wish to thank staff from the NHS Grampian genetics team and the ORCADES Study for their contribution to these datasets, in particular, Barbara Gibbons for genetic counselling of family members, the NHS Grampian genomics laboratory team for finding and testing for the variant in the clinically ascertained cases, and Laura Taylor of NHS Grampian and the Public Health Scotland genealogy team for assembling the clinical pedigree. ORCADES DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. ORCADES Sanger sequencing was performed by Camilla Drake and the technical services team at the MRC HGU. Emily Weiss and Reka Nagy assembled the ORCADES pedigree using records at the General Register Office and study information, building on earlier pedigree work by Ruth McQuillan and Jim Wilson (45). Regeneron Genetics Center performed the exome sequencing. We thank Thibaud Boutin for phasing the GSA chip data and Kiera Johnston for help with analysis of other cancer susceptibility genes. The data in the EHR was provided by patients and collected by the NHS as part of their care and support. The authors acknowledge the support of the eDRIS Team (Public Health Scotland) for their involvement in obtaining approvals, provisioning and linking this data.
We would also like to acknowledge the invaluable contributions of the research nurses in Orkney and the administrative team in Edinburgh. Finally and most importantly, we thank the people of Orkney for their involvement in and ongoing support for our research.
This work was funded by the MRC University Unit award to the MRC Human Genetics Unit, University of Edinburgh, MC_UU_00007/10. LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276 and CZB/4/710), a Royal Society URF to JFW and Arthritis Research UK.
- breast cancer
- rare variants