Clinical case study meets population cohort: Identification of a BRCA1 pathogenic founder variant in Orcadians

Shona M. Kerr, Emma Cowan, Lucija Klaric, Christine Bell, Dawn O'Sullivan, David Buchanan, Joseph J. Grzymsk, Cristopher V. van Hout, Gannie Tzoneva, Alan R. Shuldiner, James F Wilson, Zosia Miedzybrodzka* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


We multiply ascertained the BRCA1 pathogenic missense variant c.5207T>C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2,088
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.
Original languageEnglish
Pages (from-to)588-595
Number of pages7
JournalEuropean Journal of Human Genetics
Early online date16 Mar 2023
Publication statusPublished - May 2023

Bibliographical note

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


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