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 available on a clinical basis 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.

Proteus syndrome is characterized by progressive, segmental or patchy overgrowth of diverse tissues of all germ layers, most commonly affecting the skeleton, skin, adipose, and central nervous systems. In most individuals Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism.

The diagnosis of Proteus syndrome is based on clinical criteria that include three general characteristics and a specific symptom checklist. A mosaic somatic mutation of AKT1 has been identified in more than 90% of individuals meeting diagnostic criteria.

All individuals with clinically confirmed Proteus syndrome known to these authors have been simplex cases caused by somatic mosaicism for the specific de novo mutation c.49G>A (p.Glu17Lys). It is hypothesized that a nonmosaic (i.e., germline) AKT1 c.49G>A mutation would be lethal in early development. There is no known risk to offspring of an affected individual; however, the number of affected individuals who have reproduced is very small. Thus, the risks to the parents of an affected child and to affected persons who do reproduce are not increased compared to the general population. Because Proteus syndrome is not inherited, prenatal testing is not indicated.