Prevalence of five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families

Abstract

Many rearrangement mutations in the BRCA1 gene have been identified. It is becoming clear that some of these mutations are prevalent, and therefore their detection is necessary in order for clinical genetic tests to have high sensitivity. Published information on particular rearrangements is frequently limited to a single patient, small groups of patients, or patients of a particular ethnicity. The objectives of this work included characterizing the prevalence of five specific rearrangement mutations in a large North American patient population. A mutation-specific multiplex PCR assay was used for determining the prevalence of five BRCA1 rearrangement mutations that previously had been reported to occur in unrelated patients. The mutation status of these rearrangements, which came from 20,712 patients at high risk for hereditary breast and/or ovarian cancers who had submitted specimens for clinical genetic testing, is presented. The results, obtained from 2,634 mutation carriers, showed a 6-kb duplication of exon 13, identified in 53 patients (2.01%); a 26-kb deletion encompassing exons 14-20, detected in seven patients (0.27%); a 510-bp deletion of exon 22, detected in 5 patients (0.19%); and a 3.4-kb deletion of exon 13, detected in one patient (0.04%). A previously reported 7.1-kb deletion of exons 8-9 was not found. The high frequency of the exon 13 duplication makes it the fourth most prevalent mutation in these patients. These results provide an accurate picture of the prevalence of these mutations in hereditary breast/ovarian cancer patients undergoing genetic testing in North America.

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

“…Our results confirmed the higher prevalence of rearrangements in the BRCA1 gene versus the BRCA2 gene documented in previous reports (21)(22)(23)(24)(25).…”

MLPA screening in theBRCA1gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases

“…In total, 45 intragenic deletions, duplications, or losses of promoter region could be demonstrated in 1,700 families found to be negative for BRCA mutations after screening with PCRbased techniques. The overall frequency of BRCA1 rearrangements (2.1%) in German high-risk families as identified in this study is comparable with the results reported for North Americans [Hendrickson et al, 2005], Australians [Woodward et al, 2005], or Eastern Asians [Lim et al, 2007], but is significantly lower than that reported for the Dutch [Hogervorst et al, 2003], Northern Italian [Montagna et al, 2003], French , or Czech population [Vasickova et al, 2007]. Similar low prevalences have been also reported for the Finnish [Laurila et al 2005] and Danish population [Thomassen et al 2006].…”

Mutator Phenotype ofCaenorhabditis elegansDNA Damage Checkpoint Mutants

“…A recent study of BRCA1 and BRCA2 tumors revealed a number of large hemizygous deletions based on comparative genome hybridization using microarrays with an average resolution of 1 Mb ( Jonsson et al 2005). Further, the second allele of BRCA1 or BRCA2 is almost always inactivated by genomic rearrangements or deletions in cancers that develop in patients who are heterozygous at one of these loci (Welcsh and King 2001;Hendrickson et al 2005). Although we recovered one visible mutant from a mrt-2 background with an $230-kb deletion, mrt-2 and clk-2(mn159) defects resulted in 22 additional spontaneous deletions that ranged from 0.15 to 35 kb.…”