Thompson & Thompson Genetics in Medicine, 8th Edition

Case 7. Hereditary Breast and Ovarian Cancer (BRCA1 and BRCA2 Mutations)

Autosomal Dominant


• Tumor-suppressor gene

• Multistep carcinogenesis

• Somatic mutation

• Incomplete penetrance and variable expressivity

• Founder effect

Major Phenotypic Features

• Age at onset: Adulthood

• Breast cancer

• Ovarian cancer

• Prostate cancer

• Multiple primary cancers

History and Physical Findings

S.M., a 27-year-old previously healthy woman, was referred to the cancer genetics clinic by her gynecologist after being diagnosed with breast cancer. She was concerned about her children's risk for development of cancer and about her risk for development of ovarian cancer. Her mother, two maternal aunts, and maternal grandfather had breast cancer; her mother had also had ovarian cancer (Fig. C-7). The genetic counselor explained that the family history of breast cancer was indicative of an inherited predisposition and calculated that the proband's risk for carrying a mutation in the breast cancer susceptibility gene BRCA1 or BRCA2 was well above the threshold for considering gene sequencing. On the basis of the ensuing discussion of prognosis and recurrence risks, S.M. chose to pursue DNA sequencing of BRCA1and BRCA2. This testing showed that she had a premature termination mutation in one BRCA2 allele that had been previously seen in other patients with early-onset breast cancer. During the discussion of the results, S.M. inquired whether her 6- and 7-year-old girls should be tested. The genetic counselor explained that because the mutations posed little risk in childhood, the decision to have genetic testing was better left until the children were mature enough to decide on the utility of such testing, and S.M. agreed.


FIGURE C-7 Family segregating a BRCA2 C3590G mutation. The proband, S.M., is indicated by an arrowBlue symbols indicate a diagnosis of cancer. Ages are shown directly below the symbol. A plus sign identifies carriers of the BRCA2 mutation, and a minus sign identifies noncarriers as determined by DNA sequencing. Cancer diagnoses are followed by the age at diagnosis. Cancer abbreviations: Br, breast; Lu, lung; Ov, ovarian; Pa, pancreatic; Pr, prostate. Other abbreviations: Bso, bilateral salpingo-oophorectomy; d., age at death; Px Bmx, prophylactic bilateral mastectomy. See Sources & Acknowledgments.

Five adult relatives elected to have predictive testing, and four (including one male) were found to be carriers of the mutation; one of these four, a female, pursued prophylactic bilateral mastectomy. The risk for cancers at other sites was also discussed with all mutation carriers.


Disease Etiology and Incidence

Mutations of major cancer predisposition genes account for 3% to 10% of cases of breast cancer and have an estimated overall prevalence of 1 in 300 to 1 in 800. Two of these genes are BRCA1 and BRCA2. In the general North American population, the prevalence of BRCA1 mutations is between 1 in 500 and 1 in 1000; the prevalence of BRCA2 mutations is approximately twice as high. There are, however, marked differences in ethnic distribution of deleterious mutations among families with two or more cases of breast or ovarian cancer. Mutations of BRCA1 or BRCA2 account for approximately 70% to 80% of familialbreast cancer cases but only a small fraction of breast cancer overall (see Chapter 15).


BRCA1 and BRCA2 encode ubiquitously expressed nuclear proteins that are believed to maintain genomic integrity by regulating DNA repair, transcriptional transactivation, and the cell cycle.

Despite the ubiquitous expression of BRCA1 and BRCA2, mutation of these genes predisposes predominantly to breast and ovarian neoplasias. Loss of BRCA1 or BRCA2 function probably permits the accumulation of other mutations that are directly responsible for neoplasia. Consistent with this hypothesis, breast and ovarian carcinomas from patients with mutations of BRCA1 or BRCA2 have chromosomal instability and frequent mutations in other tumor-suppressor genes.

Tumor formation in carriers of BRCA1 or BRCA2 germline mutations follows the two-hit hypothesis; that is, both alleles of either BRCA1 or BRCA2 lose function in tumor cells (see Chapter 15). Somatic loss of function by the second allele can occur by a variety of mechanisms, including loss of heterozygosity, intragenic mutation, or promoter hypermethylation. Because of the high frequency with which the second allele of BRCA1 or BRCA2 loses function, families segregating a germline BRCA1 or BRCA2 mutation exhibit autosomal dominant inheritance of neoplasia.

The population prevalence of individual BRCA1 or BRCA2 germline mutations varies widely and often suggests a founder effect. In Iceland, the BRCA2 999del5 mutation occurs on a specific haplotype and has a prevalence of 0.6% in that population. Among Ashkenazi Jews, the BRCA1 185delAG and 5382insC mutations and the BRCA2 6174delT mutation also occur on specific haplotypes and have prevalences of 1%, 0.4%, and 1.2%, respectively.

Phenotype and Natural History

Patients with BRCA1 or BRCA2 germline mutations have an increased risk for several cancers (see Table). In addition to the increased risk for ovarian and female breast cancer, BRCA1 mutations confer an increased risk for prostate cancer, melanoma, and possibly for colon cancer. Similarly, in addition to ovarian and female breast cancer, germline BRCA2 mutations increase the risk for prostate, pancreatic, bile duct, gallbladder, melanoma, and male breast cancers.

Among female carriers of a BRCA1 or BRCA2 germline mutation, the overall penetrance of breast cancer, ovarian cancer, or both is estimated to be approximately 50% to 80% for BRCA1 mutations but lower for BRCA2 mutations (40% for breast cancer and 10% for ovarian cancer). Approximately two thirds of families with a history of breast and ovarian cancer segregate a BRCA1 mutation, whereas approximately two thirds of families with a history of male and female breast cancer segregate a BRCA2 mutation.


Current recommendations for women with a germline BRCA1 or BRCA2 mutation include frequent breast and ovarian examinations as well as imaging studies. Management of at-risk males includes frequent prostate and breast examinations and laboratory tests for evidence of prostate cancer. In families with known germline mutations, molecular analysis can focus surveillance or prophylaxis on members carrying a mutation. Total bilateral mastectomy may reduce the risk for breast cancer by more than 90%, although the risk is not abolished because some breast tissue often remains. Similarly, bilateral salpingo-oophorectomy may reduce the risk for ovarian cancer by more than 90%.

Inheritance Risk

Female sex, age, and family history are the most important risk factors for breast cancer. In Western populations, the cumulative female breast cancer incidence is 1 in 200 at 40 years, 1 in 50 at 50 years, and 1 in 10 by 70 years. If patients have a first-degree relative in whom breast cancer developed after 55 years, they have a 1.6 relative risk for breast cancer, whereas the relative risk increases to 2.3 if the breast cancer developed in the family member before 55 years and to 3.8 if it developed before 45 years. If the first-degree relative had bilateral breast cancer, the relative risk is 6.4.

Children of a patient with a BRCA1 or BRCA2 germline mutation have a 50% risk for inheriting that mutation. Because of incomplete penetrance and variable expressivity, the development and onset of cancer cannot be precisely predicted.

Cumulative Risk (%) by Age 70 Years


Questions for Small Group Discussion

1. At what age and under what conditions might testing of an at-risk child be appropriate?

2. What is the risk for development of prostate cancer in a son if a parent carries a BRCA1 germline mutation? A BRCA2 germline mutation?

3. Currently, sequencing of the coding region of BRCA1 detects only 60% to 70% of mutations in families with linkage to the gene. What mutations would sequencing miss? How should a report of “no mutation detected by sequencing” be interpreted and counseled? How would testing of an affected family member clarify the testing results?


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Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2013;105:812–822.

Metcalfe KA, Kim-Sing C, Ghadirian P, et al. Health care provider recommendations for reducing cancer risks among women with a BRCA1 or BRCA2 mutation. Clin Genet. 2014;85:21–30.