title: Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer.
abstract: BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 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 BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results.
  
  
  CONCLUSIONS
  Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.
authors.affiliation: Abramson Cancer Center, Department of Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA. susan.domchek@uphs.upenn.edu
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Tang
authors.forename: Jill
authors.initials: J
authors.lastname: Stopfer
authors.forename: Dana R
authors.initials: DR
authors.lastname: Lilli
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
authors.forename: Troy E
authors.initials: TE
authors.lastname: Messick
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Powers
authors.forename: Alexandria
authors.initials: A
authors.lastname: Yonker
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: H Rosemarie
authors.initials: HR
authors.lastname: Davidson
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
mesh_terms: D000328:Adult; D000483:Alleles; D002291:Carcinoma, Papillary / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*