Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Breast Cancer, familial [C50.9]

OMIM numbers: 114480113705 (BRCA1), 600185 (BRCA2)

Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

About 5–10% of all breast and ovarian carcinomas are hereditary with autosomal dominant inheritance. Significant characteristics of the hereditary form of this disease are an early age at onset (before the fifth decade of life) and multiple affected individuals in a family. The genes BRCA1 and BRCA2 are causal for about 50% of inherited breast and ovarian cancers. The gene products of BRCA1 and BRCA2 are involved in DNA repair of double-strand breaks. Female carriers of a BRCA germline mutation always bear an increased lifetime risk to develop breast and ovarian cancer. However, a tumor only develops if the second intact allele is inactivated by mutation or allelic loss (transition from germ-line heterozygosity to somatic homozygosity: loss of heterozygosity, LOH). The risk of developing breast cancer is between 50 and 80%, for contralateral breast cancer 60% and between 10 and 40% for ovarian cancer. Male carriers of BRCA mutations also bear an increased tumor risk, especially for breast, prostate, pancreatic, stomach and colorectal carcinomas. However, in male patients mutations in the BRCA2 gene are more frequent.

Women of older age that develop breast cancer and do not have any further affected family members are most likely no mutation carriers. For women that have a family with more members affected by breast or ovarian cancer or with very early onset of disease, genetic testing may be advisable. This is why inclusion criteria were established in Germany with a mutation detection probability in the genes BRCA1 and BRCA2 of over 10% (see indication). A causal mutation can be identified in about 25% of all families who meet the criteria.

For secondary prevention, structured multimodal screening programs are recommended in Germany to female patients with an identified mutation and to women with families that were tested BRCA1/2 negative with a heterozygous risk of ≥20% or a lifetime risk of ≥30% to develop disease. Primary prevention includes prophylactic surgery which should be explained to affected patients in the course of interdisciplinary counselling.

In predictive genetic testing, at-risk, asymptomatic individuals are tested, usually first-degree relatives of affected patients. According to the Genetic Diagnosis Act (GenDG) genetic counseling should be offered along with any genetic diagnostic procedure. In the case of predictive genetic testing, genetic counseling must be carried out prior to testing as well as after having received the result, unless there exists a written waiver of the at-risk person after having received written information on the content of the counseling.