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

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Breast and Ovarian Cancer, familial - Advanced Diagnostics

OMIM numbers: 604370113705 (BRCA1), 600185 (BRCA2), 607585 (ATM), 192090 (CDH1), 604373 (CHEK2), 602667 (NBN), 610355 (PALB2), 191170 (TP53), 602774 (RAD51C), 602954 (RAD51D)

Dipl.-Biol. Anne Holtorf, Dr. biol. hum. Stefanie Kühner

Scientific Background

Every 8-10 women will suffer from breast cancer at some point in their lifetime; in 2012 in Germany alone there were around 74,000 new cases. Approximately 7,200 women developed ovarian cancer in the same period. About 5-10% of all breast and ovarian carcinomas are hereditary with autosomal dominant inheritance. Characteristics of the hereditary form are an early age at onset (before the fifth decade of life) and multiple occurrence within a family. Since in these cases, genetic testing may be indicated, criteria have been defined for those people with at least a 10% probability of having a mutation in the genes BRCA1 and BRCA2 (Table 1). Although in fact, in up to 25% of families that meet these criteria, a causal mutation can be identified (Meindl et al, Medgen 25: 259 (2013)).


Female carriers of a germline mutation in a “breast cancer gene” have an increased lifetime risk of developing cancer. However, a tumor only develops if the second intact allele is inactivated by mutation (loss of heterozygosity, LOH). With a known BRCA1 mutation, the risk of developing breast cancer is between 60 and 85%, for bilateral breast cancer it is 15-40% and 45% for ovarian cancer. With a known BRCA2 mutation, the risk of developing breast cancer is between 40 and 85%, for bilateral breast cancer it is 15-40% and between 15-20% for ovarian cancer. Male carriers of BRCA mutations also have an increased tumor risk, especially for breast, prostate, pancreatic, stomach and colorectal carcinomas. In male patients, mutations are most often found in the BRCA2 gene.

As well as BRCA1 and BRCA2, further genes have been identified, in which mutations or variants are also associated with an increased disease risk. The German Consortium - Familial Breast and Ovarian Cancers (GC-HBOC) recently proposed a further 8 “core genes” (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53) to be included in advanced diagnostics. However, since their disease association is weaker, findings with unclear clinical relevance are to be expected and the patient must be informed accordingly. See Table 1 for criteria for advanced diagnostics.

The genes RAD51C/D are altered in approximately 1.5% of all familial breast and ovarian cancers with moderately more penetrating effect and lead to 6-fold increased risk of ovarian carcinoma. An ATM or NBN mutation increases the risk of breast cancer by a factor of 2.4. Mutations in the PALB2 gene are found in approximately 1% of breast cancer patients, and are associated with an 8-fold increase in disease risk (Antoniou et al, N Engl J Med 371:497, 2015). Pancreatic carcinoma is also observed in clusters. Mutations in CHEK2 gene also increase the breast cancer risk 2-3 times, here the deletion c.1100delC is the most common mutation, identified in approximately 4% of hereditarily predisposed families. This deletion also increases the prostate cancer risk in men. Mutations in the CDH1 gene cause hereditary diffuse gastric cancer and an association with lobular breast cancer has been described. Mutations in the TP53 gene cause Li-Fraumeni syndrome and are associated with a significantly increased risk of breast cancer. All affected genes play a role in DNA double-strand break repair. The lifetime risk of disease for mutation carriers is given in Table 2.


In Germany, a structured screening program is recommended for women with a confirmed mutation in BRCA1/2 and women from families tested BRCA1/2 negative with a heterozygous risk of > 20%, or a lifetime risk of developing disease of > 30%. Furthermore, there is the possibility of prophylactic surgery which should be explained to affected patients in the course of interdisciplinary consultation and support.

Recommendations for intensive screening in the case of mutations in the 10 core genes are given in Table 3 (modified from Meindl et al, Medgen 2:202, 2015).


In predictive genetic testing, at-risk, healthy individuals are tested, being usually first-degree relatives of affected patients. According to the German Gene Diagnostic Act (GenDG), genetic counseling should be offered with any diagnostic genetic test. In the case of predictive genetic testing, genetic counseling must be carried out prior to testing as well as after having received the result. At this time, only the testing of high risk genes BRCA1/2, is a standard benefit of health insurance companies. The advanced diagnostics of the additional 8 “core genes” can only be carried out with a declaration of cost absorption from the health insurance company, or in special cases as part of a clinical study.