A germline mutation in BRCA1 or BRCA2 predisposes to breast and ovarian cancer as well as other cancers. The risk of developing cancer that is associated with a germline BRCA1 or BRCA2 mutation, which has been derived from families with multiple affected individuals, families with few affected individuals, and from population-based studies, appears to be variable within families. Prognosis for breast and ovarian cancer depends on the stage at which the cancer is diagnosed; however, studies on survival have revealed conflicting results for individuals with germline BRCA1 or BRCA2 mutations when compared to controls.

Molecular genetic testing for germline BRCA1 and BRCA2 mutations is possible for individuals who are identified to be at high risk based on their personal and/or family history and for at-risk relatives of an individual with an identified germline BRCA1 or BRCA2 mutation. No currently available technique can guarantee the identification of all cancer-predisposing mutations in BRCA1 or BRCA2. Furthermore, mutations of uncertain clinical significance may be identified.

Germline mutations in BRCA1 and BRCA2 are inherited in an autosomal dominant manner. Each offspring of an individual with a BRCA1 or BRCA2 germline mutation has a 50% chance of inheriting the mutation. Molecular genetic testing of asymptomatic family members at risk of inheriting either a BRCA1 or BRCA2 germline mutation is feasible once the family-specific mutation has been identified. Prenatal testing is possible for pregnancies at increased risk if the cancer-predisposing mutation in the family is known; however, requests for prenatal diagnosis of adult-onset diseases are uncommon and require careful genetic counseling.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of the following classic tumors: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. In addition, a variety of other neoplasms may occur. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers. Age-specific cancer risks have been calculated.

LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline mutation in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline mutation in TP53, the only gene so far identified in which mutations are definitively associated with LFS.

LFS is inherited in an autosomal dominant manner. The proportion of individuals with a de novo germline TP53 mutation is estimated to be between 7% and 20%. Offspring of an affected individual have a 50% chance of inheriting the deleterious mutation. Predisposition testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the heritable mutation in the family has been identified.