De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer

Abstract

Germline mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ ovarian cancer. Identification of breast cancer patients carrying mutations of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of the disease or both. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary breast/ovarian cancer, we identified a germline mutation in the BRCA2 gene (3034del4) in a patient with early onset breast cancer and no strong family history of the disease. Subsequent molecular analysis in her parents showed that neither of them carried the mutation. Paternity was confirmed using a set of highly polymorphic markers, showing that the proband carried a de novo germline mutation in the BRCA2 gene. Interestingly, 3034del4 is a recurrent mutation occurring in a putative mutation prone region of the BRCA2 gene. Our study presents the first case in which a de novo germline mutation in the BRCA2 gene has been identified, and supports previous results of haplotype studies, confirming that the 3034del4 mutation has multiple independent origins. (J Med Genet 2001;38:102-105)

A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer

“…The result suggests a de novo event in a testicular germ cell, although an occurrence in the zygote can not be discarded. This is in agreement with previous findings in de novo mutations in BRCA1 and BRCA2, in which the paternal origin could be ascertained [5,8], and also in other hereditary cancer syndromes (neurofibromatosis type 1, MEN2B and retinoblastoma) [10,11]. It has been suggested that the origin of new mutations may be influenced by both genomic imprinting effects and the increased number of cell divisions in spermatogenesis compared with oogenesis.…”

“…Despite the high number of mutations identified and the large number of studies carried out world wide, to our knowledge there is only one published report of a de novo mutation in BRCA1 [6] and three in BRCA2 [7][8][9].…”

“…As an example, the BRCA2 c.3036_3039del4 mutation may have arisen on many separate occasions in various ethnic groups, according to the results of haplotype studies, and it has also been identified as a de novo mutation [8]. The authors suggested that these occurrences could be related with tandemly repeated sequences, which favor misalignments during DNA replication.…”

Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2

“…The exact number of individuals with a BRCA1 or BRCA2 mutation that has occurred as a de novo event is not known but is believed to be small. [167][168][169] Risk to siblings of a proband with a BRCA1/2 mutation The risk to full siblings of an individual with a mutation in BRCA1 or BRCA2 depends on the genetic status of their parents. If one parent has the BRCA1 or BRCA2 mutation, then the risk for siblings to also carry the family-specific mutation is 50%.…”

Two founder BRCA2 mutations predispose to breast cancer in young women

“…3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 9 These mutations also contribute to clarify the workflow to launch in Spanish families, reducing costs and accelerating the diagnosis in high risk BOC families. Based on these results, we can define a panel of four BRCA2 Spanish proven founder mutations together with the highly prevalent BRCA2-3036delACAA (a priori of multiple origin) [18] that would allow to identify nearly 50% of BRCA2+ families with only 5 PCR reactions. Furthermore, in these mutations associated with early breast cancer it is essential to detect rapidly asymptomatic carriers who may benefit from prevention protocols since survival rates of breast cancer are worse than in older women.…”