Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study

Susan L. Neuhausen, Andrew K. Godwin, Ruth Gershoni-Baruch, Elizabeth Schubert, Judy Garber, Dominique Stoppa-Lyonnet, Edith Olah, Bela Csokay, Olga Serova, Fiona Lalloo, Ana Osorio, Michael Stratton, Kenneth Offit, Jeff Boyd, M. Adelaide Caligo, Rodney J. Scott, Andy Schofield, Eric Teugels, Manfred Schwab, Lisa Cannon-AlbrightTimothy Bishop, Douglas Easton, Javier Benitez, Mary Claire King, Bruce A.J. Ponder, Barbara Weber, Peter Devilee, Åke Borg, Steven A. Narod, David Goldgar

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Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in ~1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 muta- tions. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P = .10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P < .001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P = .0005).

Original languageEnglish
Pages (from-to)1381-1388
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - jún. 1998


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garber, J., Stoppa-Lyonnet, D., Olah, E., Csokay, B., Serova, O., Lalloo, F., Osorio, A., Stratton, M., Offit, K., Boyd, J., Caligo, M. A., Scott, R. J., Schofield, A., Teugels, E., Schwab, M., ... Goldgar, D. (1998). Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study. American Journal of Human Genetics, 62(6), 1381-1388. https://doi.org/10.1086/301885