Table 1 NCCN recommendation for gene specific risk assessment, high risk surveillance plan and prophylactic surgery for associated malignancy risk. Table adapted from NCCN Guidelines (version 2.2021) [9]
Gene | Evidence for increased risk | Absolute risk (%) | Other cancer risks and syndromes | Breast cancer management | Other cancers management |
|---|---|---|---|---|---|
BRCA1 | Very strong (with predisposition to triple-negative disease) | > 60 | Ovarian cancer Pancreatic cancer Prostate cancer | Breast awareness starting at 18 months Clinical breast exam, every 6–12 months, starting at 25 years of age Annual breast MRI screening Discuss option of RRM Annual mammogram screening in men with gynecomastia at age 50 or 10 years before the earliest known male breast cancer in the family | Recommend RRBSO typically at 35–40 years of age If no RRBSO, then TVUS with serum CA-125 for ovarian cancer screening starting at 30–35 years Consider prostate cancer screening in men starting at age 40 years Pancreatic cancer screening using contrast enhanced MRI/MRCP or EUS |
BRCA2 | Very strong (with predisposition to ER+ disease) | > 60 | Ovarian cancer Pancreatic cancer Prostate cancer Melanoma | Breast awareness starting at 18 months Clinical breast exam, every 6–12 months, starting at 25 years of age Annual breast MRI screening Discuss option of RRM Annual mammogram screening in men with gynecomastia at age 50 or 10 years before the earliest known male breast cancer in the family | Recommend RRBSO typically at 40–45 years of age If no RRBSO, then TVUS with serum CA-125 for ovarian cancer screening starting at 30–35 years Recommend prostate cancer screening in men starting at age 40 years Pancreatic cancer screening using contrast enhanced MRI/MRCP or EUS |
ATM | Strong | 15–40 | Ovarian cancer Pancreatic cancer Ataxia telangiectasia | Screening with annual mammogram with consideration for tomosynthesis and consider breast MRI with contrast starting at age 40 years Insufficient evidence for RRM, manage based on FH | Insufficient evidence for RRBSO, manage based on FH Screening mutation carriers with a family history of pancreatic cancer |
CHECK2 | Strong | 15–40 | Colon cancer | Screening with annual mammogram with consideration for tomosynthesis and consider breast MRI with contrast starting at age 40 years Insufficient evidence for RRM, manage based on FH | Colon cancer surveillance is recommended same as APC which is colonoscopy (preferred) or flexible sigmoidoscopy every 12 months starting at age 10–15 years |
NF1 | Strong | 15–40 | Malignant peripheral nerve sheath tumors, GIST, others | Screening with annual mammogram with consideration for tomosynthesis starting at age 30 years and consider breast MRI with contrast from ages 30–50 years Insufficient evidence for RRM, manage based on FH | Recommend referral to NF1 specialist for evaluation and management of other associated tumors |
CDH1 | Strong | 41–60 | Hereditary diffuse gastric cancer | Screening with annual mammogram with consideration for tomosynthesis and consider breast MRI with contrast starting at age 30 years Insufficient evidence for RRM, manage based on FH | Prophylactic total gastrectomy for CDH1 mutation carriers is recommended between ages 18 and 40 years and earlier than 18 years if gastric cancer in a family member before 25 years of age If patient elects not to undergo gastrectomy, screen every 6–12 months by upper endoscopy with multiple random biopsies |
PALB2 | Strong | 41–60 | Ovarian cancer Pancreatic cancer (limited increased risk) | Screening with annual mammogram with consideration for tomosynthesis and breast MRI with contrast starting at age 30 years Discuss option of RRM | For ovarian cancer management there is insufficient evidence, managed based on FH Screening mutation carriers with a family history of pancreatic cancer |
PTEN | Strong | 41–60 | Thyroid cancer Colon cancer Endometrial cancer Cowden syndrome | Women: Screening with annual mammogram with consideration for tomosynthesis and breast MRI with contrast starting at age 30–35 years or 5–10 years before the earliest known breast cancer in the family Discuss option for RRM | Start endometrial cancer screening by age 35 years, patient education regarding AUB and symptoms is important, consider endometrial biopsy every 1–2 years Discuss option of hysterectomy upon completion of family Men and Women: Annual thyroid U/S starting at age 7 years Colonoscopy starting at age 35 years unless symptomatic or if close relative with colon cancer, then start 5–10 years before the earliest known colon cancer in the family Consider renal U/S starting at age 40 years, then every 1–2 year Annual dermatology exams for melanoma |
STK11 | Strong | 41–60 | Ovarian (non-epithelial) cancer Pancreatic cancer Peutz-Jeghers syndrome | Evidence insufficient for RRM, manage based on FH Peutz-Jeghers syndrome management: Clinical breast exam every 6 months, with annual mammogram and breast MRI starting at 30 years of age | Colonoscopy and upper endoscopy every 2–3 years starting in late teens Small bowel visualization (CT or MRI enterography or video capsule endoscopy baseline starting at age 8–10 years, then every 2–3 years Pancreatic cancer screening using contrast enhanced MRI/MRCP or EUS Annual physical examination for observation of precocious puberty starting at 8 years Pelvic examination and pap smear annually starting 18–20 years Annual testicular exam and observation for feminizing changes starting at 10 years |
TP53 | Strong | > 60 | Pancreatic cancer (limited) Li-Fraumeni syndrome | Screening with annual mammogram with consideration for tomosynthesis and breast MRI with contrast Discuss option of RRM | Colonoscopy and upper endoscopy every 2–5 years starting at 25 years or 5 years before the earliest known colon cancer in the family Annual dermatological examination starting at 18 years Annual whole-body MRI including brain Screening mutation carriers with a family history of pancreatic cancer |
BARD1 | Limited (but stronger with triple negative disease) | Insufficient data | None | Screening with annual mammogram with consideration for tomosynthesis and consider breast MRI with contrast starting at age 40 Insufficient evidence for RRM, manage based on FH | Â |
BRIP1 | Limited; potential increase in female breast cancer (including triple negative disease) | Insufficient data | Ovarian cancer | Insufficient data for breast cancer management, managed based on FH | Consider RRSO at 45–50 years of age |
NBN | No increased risk except 657del5 mutation which has mixed evidence | Insufficient data | Limited risk for Ovarian cancer | Insufficient data for breast cancer management, managed based on FH | Ovarian cancer management also based on FH |
MSH2 MLH1 MSH6 PMS2 EPCAM | Limited | < 15 | Ovarian cancer Pancreatic cancer (excluding PMS2) Colon, Uterine and others Lynch syndrome | Insufficient data for breast cancer management, managed based on FH | Screening mutation carriers with a family history of pancreatic cancer Other management is under Lynch syndrome management requires surveillance in accordance with the mutated gene |
RAD51C | Limited; potential increase in female breast cancer (including triple negative disease) | 15–40 | Ovarian cancer | Insufficient data for breast cancer management, managed based on FH | Consider RRSO at 45–50 years of age |
RAD51D | Limited; potential increase in female breast cancer (including triple negative disease) | 15–40 | Ovarian cancer | Insufficient data for breast cancer management, managed based on FH | Consider RRSO at 45–50 years of age |
CDKN2A | None | – | Pancreatic cancer Melanoma | – | Pancreatic cancer screening using contrast enhanced MRI/MRCP or EUS |