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

AbstractThe BRCA1 pathogenic missense variant c.5207T>C; p.Val1736Ala (V1736A) was multiply ascertained in the clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. 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. Fourteen mutation carriers were identified from predictive tests in relatives of affected members of the index kindred, nine more from NHS diagnostic testing plus a further six obligate carrier females. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2,090 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 2,090 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 a single BRCA1 founder mutation 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 mutation, starting with those with ancestry from Westray.