Counselling framework for moderate-penetrance cancer-susceptibility mutations.
The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2-5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high-penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch syndrome). The extrapolation of guidelines for the management of individuals with high-penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-penetrance gene mutations associated with an increased risk of cancer.
Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Nadine
N
Tung
Abramson Cancer Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA, and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Susan M
SM
Domchek
Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; and the Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
Zsofia
Z
Stadler
Abramson Cancer Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA, and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Katherine L
KL
Nathanson
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street South West, Rochester, Minnesota 55905, USA.
Fergus
F
Couch
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Judy E
JE
Garber
Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; and the Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
Kenneth
K
Offit
Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; and the Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
Mark E
ME
Robson
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000517:prevention & control; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008327:Mammography / Q000379:methods; D008408:Mastectomy / Q000379:methods; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000517:prevention & control; D019683:Penetrance; D012307:Risk Factors