REVIEW

Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2

Blanche P Alter¹, Philip S Rosenberg², Lawrence C Brody³

¹ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
² Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
³ Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA

Correspondence to:
Dr B P Alter
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Executive Plaza South, Room 7020, Rockville, MD 20852-7231, USA; alterb{at}mail.nih.gov

Patients with biallelic mutations in BRCA2 are in Fanconi anaemia group D1. We analysed the severity of the mutations in 27 cases, classified according to their association with breast cancer in heterozygotes, and their predicted functional effect. Twenty mutations were frameshifts or truncations, three involved splice sites, five were missense variants of unknown severity and two were benign polymorphisms. Five patients had VACTERL-H association. Leukaemia was reported in 13 patients, and solid tumours in 15; 6 patients had two or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1GA and IVS7+2TG were associated with AML, and 886delGT and 6174delT with brain tumours. However, patients with other alleles remained at very high risk of these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein.

The small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, and early onset and high rates of leukaemia and specific solid tumours, and may comprise an extreme variant of Fanconi anaemia. Several of the alleles were not associated with cancer in presumed carriers, and thus counselling presents more uncertainties than usual.

Abbreviations: AML, acute myelogenous leukaemia; BIC, Breast Cancer Information Core; HBOC, hereditary breast/ovarian cancer; VACTERL-H (V, vertebral; A, anal atresia; C, cardiac; TE, tracheoesophageal fistula, oesophageal atresia; R, renal or radial; L, limb anomalies; H, hydrocephalus)

Keywords: tumour

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