Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: The WECARE study Journal Article
| Authors: | Borg, A.; Haile, R. W.; Malone, K. E.; Capanu, M.; Diep, A.; Törngren, T.; Teraoka, S.; Begg, C. B.; Thomas, D. C.; Concannon, P.; Mellemkjaer, L.; Bernstein, L.; Tellhed, L.; Xue, S.; Olson, E. R.; Liang, X.; Dolle, J.; Børresen-Dale, A. L.; Bernstein, J. L.; Reiner, A. S.; Layne, T. M.; Donnelly-Allen, L.; Olsen, J. H.; Andersson, M.; Bertelsen, L.; Guldberg, P.; Epstein, N.; Boice, J. D. Jr; Seminara, D.; Shore, R. E.; Jansen, L.; Anton-Culver, H.; Largent, J.; Lynch, C. F.; DeWall, J.; Langholz, B. M.; Zhou, N.; Diep, A. T.; Ter-Karapetova, E.; Thompson, W. D.; Stovall, M.; Smith, S.; Ramchurren, N. |
| Article Title: | Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: The WECARE study |
| Abstract: | BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. ©2010 Wiley-Liss, Inc. |
| Keywords: | adult; controlled study; gene mutation; gene sequence; major clinical study; gene deletion; missense mutation; breast cancer; genetic variability; gene frequency; brca1 protein; brca2 protein; risk; oncogene; algorithm; population; nucleotide sequence; binding site; dna binding; biochemistry; brca1; brca2; unclassified variants; contralateral; deleterious mutation |
| Journal Title: | Human Mutation |
| Volume: | 31 |
| Issue: | 3 |
| ISSN: | 1059-7794 |
| Publisher: | Wiley Liss |
| Date Published: | 2010-03-01 |
| Start Page: | E1200 |
| End Page: | E1240 |
| Language: | English |
| DOI: | 10.1002/humu.21202 |
| PROVIDER: | scopus |
| PMCID: | PMC2928257 |
| PUBMED: | 20104584 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: HUMUE" - "Source: Scopus" |
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