Data from Biallelic Deleterious <i>BRCA1</i> Mutations in a Woman with Early-Onset Ovarian Cancer

Abstract

<div>Abstract<p><i>BRCA1</i> and <i>BRCA2</i> are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in <i>BRCA2</i> can lead to Fanconi anemia and predisposition to cancers, whereas biallelic <i>BRCA1</i> mutations have not been confirmed, presumably because one wild-type <i>BRCA1</i> allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in <i>BRCA1</i>, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in <i>BRCA1</i>, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. <i>BRCA1</i> p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type <i>BRCA1</i>, and <i>BRCA1</i> p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human <i>BRCA1</i> mutations and have implications for the interpretation of genetic test results.</p><p><b>Significance:</b> Accurate assessment of genetic testing data for <i>BRCA1</i> mutations is essential for clinical monitoring and treatment strategies. Here, we report the first validated example of an individual with biallelic <i>BRCA1</i> mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy. <i>Cancer Discov; 3(4); 399–405. ©2012 AACR.</i></p><p>See related commentary by D'Andrea, p. 376</p><p>This article is highlighted in the In This Issue feature, p. 363</p></div>