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

Blanche P. Alter, Philip S. Rosenberg, Lawrence C. Brody

Research output: Contribution to journalArticle

Abstract

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+1G→A and IVS7+2T→G 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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Medical Genetics
Volume44
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

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Mutation
Fanconi Anemia
Neoplasms
Leukemia
BRCA2 Protein
Alleles
Frameshift Mutation
Missense Mutation
Heterozygote
Brain Neoplasms
Uncertainty
Complementation Group D1 Fanconi Anemia
Counseling
Breast Neoplasms
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. / Alter, Blanche P.; Rosenberg, Philip S.; Brody, Lawrence C.

In: Journal of Medical Genetics, Vol. 44, No. 1, 01.2007, p. 1-9.

Research output: Contribution to journalArticle

Alter, Blanche P. ; Rosenberg, Philip S. ; Brody, Lawrence C. / Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. In: Journal of Medical Genetics. 2007 ; Vol. 44, No. 1. pp. 1-9.
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