Recurrent BRCA2 exon 3 deletion in Assyrian families

Correspondence to Rachel Hodan, Stanford Health Care, Stanford, California, 94304, USA; [email protected]

Introduction

The BRCA2 gene (GenBank NM_000059) is a tumour suppressor gene on chromosome 13 that was identified in 1995 and maintains genome stability by DNA repair by multiple functions.¹ Pathogenic variants (PVs) in BRCA2 and another tumour suppressor gene, BRCA1 (GenBank NM_007294), cause hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant condition associated with an increased risk for female breast cancer, epithelial ovarian cancer, pancreatic cancer, melanoma, high-grade prostate cancer and male breast cancer.^{2 3}

The prevalence of BRCA1 or BRCA2 pathogenic variants is estimated to be 1 in 400 individuals.^4–6 However, in certain ethnic populations or other geographically or socially isolated groups there is a higher rate of recurrent PVs, often called founder mutations. Founder mutations in BRCA1 and BRCA2 have been described in populations worldwide including, but not limited to, European,⁷ Asian,⁸ Ashkenazi Jewish,⁹ North Africa/Middle Eastern,¹⁰ French Canadian¹¹ and Icelandic.¹² The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) recently characterised worldwide BRCA1 and BRCA2 recurrent mutations and reported more than 1700 unique BRCA2 mutations, with less than 2% characterised as a large deletion encompassing at least 1 exon and 0.1% characterised as an in-frame deletion.¹³ To our knowledge, a founder mutation in BRCA2 has not been previously described in the Assyrian population.

Assyrians are an ethnoreligious population of ancient Mesopotamia, now mostly living in modern day Iraq, Syria, Turkey and Iran. Assyrians speak modern Aramaic and adhere to different sects of Christianity.¹⁴ They may identify also as Syriac, Chaldeans or Arameans depending on their Christian affiliation. Assyrians are historically a socially isolated population with intermarriage within their community, living as a religious and language minority in mostly Muslim countries. This report aims to characterise a recurrent BRCA2 PV, exon 3 deletion, in the Assyrian population in a single centre cohort.

Case series

We identified six patients from five families with a recurrent pathogenic variant NM_000059.3 (BRCA2) exon 3 deletion. All families self-identified as Assyrian. The probands of each family presented with a classic BRCA2-associated cancer including early-onset breast cancer, epithelial serous ovarian cancer, male breast cancer and/or high-grade prostate cancer, and...