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

Shona Kerr; Emma Cowan; Lucija Klaric; Christine Bell; Dawn O'Sullivan; David Buchanan; Joseph J Grzymski; Cristopher V. van Hout; Gannie Tzoneva; Alan R. Shuldiner; James F Wilson; Zosia Miedzybrodzka

doi:10.1038/s41431-023-01297-w

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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 2088 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 2088 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 language	English
Pages (from-to)	588–595
Journal	European Journal of Human Genetics
Volume	31
Issue number	5
DOIs	https://doi.org/10.1038/s41431-023-01297-w
Publication status	Published - 16 Mar 2023

Keywords

BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
Female
Gene Frequency
Genetic Predisposition to Disease
Genetic Testing
Haplotypes
Humans
Ovarian Neoplasms/epidemiology
Scotland/epidemiology
State Medicine

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10.1038/s41431-023-01297-w

s41431-023-01297-w
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Accepted author manuscript, 499 KB

HGU Andrew Jackson RH1001
Bickmore, W.
MRC
1/04/18 → 31/03/23
Project: Research

Cite this

Kerr, S., Cowan, E., Klaric, L., Bell, C., O'Sullivan, D., Buchanan, D., Grzymski, J. J., van Hout, C. V., Tzoneva, G., Shuldiner, A. R., Wilson, J. F., & Miedzybrodzka, Z. (2023). Clinical case study meets population cohort: Identification of a BRCA1 pathogenic founder variant in Orcadians. European Journal of Human Genetics, 31(5), 588–595. https://doi.org/10.1038/s41431-023-01297-w

@article{adaef6f6b9c24ca6810b0e2d3eb4c0e6,

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

abstract = "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 2088 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 2088 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.",

keywords = "BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Testing, Haplotypes, Humans, Ovarian Neoplasms/epidemiology, Scotland/epidemiology, State Medicine",

author = "Shona Kerr and Emma Cowan and Lucija Klaric and Christine Bell and Dawn O'Sullivan and David Buchanan and Grzymski, {Joseph J} and {van Hout}, {Cristopher V.} and Gannie Tzoneva and Shuldiner, {Alan R.} and Wilson, {James F} and Zosia Miedzybrodzka",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

day = "16",

doi = "10.1038/s41431-023-01297-w",

language = "English",

volume = "31",

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journal = "European Journal of Human Genetics",

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Kerr, S, Cowan, E, Klaric, L, Bell, C, O'Sullivan, D, Buchanan, D, Grzymski, JJ, van Hout, CV, Tzoneva, G, Shuldiner, AR, Wilson, JF & Miedzybrodzka, Z 2023, 'Clinical case study meets population cohort: Identification of a BRCA1 pathogenic founder variant in Orcadians', European Journal of Human Genetics, vol. 31, no. 5, pp. 588–595. https://doi.org/10.1038/s41431-023-01297-w

TY - JOUR

T1 - Clinical case study meets population cohort: Identification of a BRCA1 pathogenic founder variant in Orcadians

AU - Kerr, Shona

AU - Cowan, Emma

AU - Klaric, Lucija

AU - Bell, Christine

AU - O'Sullivan, Dawn

AU - Buchanan, David

AU - Grzymski, Joseph J

AU - van Hout, Cristopher V.

AU - Tzoneva, Gannie

AU - Shuldiner, Alan R.

AU - Wilson, James F

AU - Miedzybrodzka, Zosia

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2023, The Author(s).

PY - 2023/3/16

Y1 - 2023/3/16

N2 - 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 2088 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 2088 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.

AB - 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 2088 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 2088 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.

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Female

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Genetic Testing

KW - Haplotypes

KW - Humans

KW - Ovarian Neoplasms/epidemiology

KW - Scotland/epidemiology

KW - State Medicine

U2 - 10.1038/s41431-023-01297-w

DO - 10.1038/s41431-023-01297-w

M3 - Article

C2 - 36927983

VL - 31

SP - 588

EP - 595

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 5

ER -

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

Abstract

Keywords

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HGU Andrew Jackson RH1001

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