Germline Mutations Associated With Increased Risk of Breast Cancer |
Gene |
Population Frequency |
% of Hereditary Cancers |
Risk by Age 70 (Penetrance) |
Type of Breast Cancer |
Other Cancers |
Involvement in Sporadic Cancers |
Comments |
BRCA1 (17q21) Hereditary breast &/or ovarian cancer syndrome |
0.1-0.3% |
˜ 50% (˜ 2% of all cancers) |
40-90% |
Majority negative for ER, PR, and HER2; basal-like, early onset |
Male breast (1-5% risk), ovary, fallopian tube, peritoneal, pancreas, cervix, uterus |
Mutations rare, may be inactivated by methylation in medullary and metaplastic |
Somatic TP53 mutations common |
BRCA2 (13q12.3) Hereditary breast &/or ovarian cancer syndrome |
0.1-0.7% |
˜ 50% (˜ 2% of all cancers) |
˜ 45-85% |
Majority positive for ER, negative for PR and HER2, “luminal B,” early or late onset |
Male breast (7% risk), ovarian, fallopian tube, peritoneal, pancreas, prostate |
Mutations and loss of expression rare |
Homozygous germline mutations cause rare form of Fanconi anemia |
TP53 (17p13.1) Li-Fraumeni syndrome |
0.0025% |
3% (< 1% of all cancers) |
> 90% |
ER positive, majority HER2 positive, “luminal B” or “HER2 enriched,” early onset |
Sarcomas, adrenal cortex, brain, leukemia, lepidic pattern lung cancer, colon |
TP53 is the most commonly mutated gene in sporadic cancers |
CDH1 (16q22.1) Familial gastric cancer and lobular breast cancer syndrome |
0.005% |
˜ 0.2-1% |
˜ 40-50% |
Lobular, ER positive, HER2 negative |
Signet ring cell gastric cancer, signet ring cell colon cancer |
Sporadic lobular carcinomas have somatic CDH1 mutations |
Very few women with lobular carcinoma have germline mutations |
PTEN (10q23.3) Cowden syndrome |
0.0005% |
˜ 0.3% |
50-85% |
No special features reported |
Male breast, thyroid, uterus |
|
10-50% of individuals may have de novo mutations |
ATM (11q22-q23) ataxia-telangiectasia heterozygotes |
0.5% |
< 1% |
˜ 30% |
No special features reported |
|
|
Homozygosity results in ataxia-telangiectasia |
CHEK2 (22q12.1) |
0.5% |
< 1-5% (˜ 1 % of all cancers) |
10-20% |
No special features reported; late onset |
Prostate, thyroid, kidney |
Mutations rare; loss of expression by unknown mechanisms |
May increase risk of breast cancer after radiation exposure |
STK11/LKB1 (19p13.3) Peutz-Jeghers syndrome |
0.001% |
˜ 0.6% |
˜ 40% |
No special features reported; early onset |
Colon, stomach, pancreas, small intestine, thyroid, lung, uterus, ovary, cervix |
|
50% of individuals may have de novo mutations |
BRIP1 (FANCJ or BACH1) (17q22.2) |
0.1% |
< 1% |
˜ 20% |
No special features reported |
|
|
Homozygosity results in Fanconi anemia |
PALB2/FANCN (16p12.1) |
0.1% |
< 1% |
˜ 20% (limited information available) |
|
Ovary, pancreas |
|
Homozygosity results in Fanconi anemia |
RAD51C (17q25.1) |
˜ 0.3% |
|
˜ 10% (limited information available) |
|
Ovary |
|
Homozygosity results in Fanconi anemia |
BARD1 (2q34-q35) |
˜ 0.5% |
|
˜ 20% (limited information available) |
|
Ovary |
RAD50 (5q31) |
˜ 0.3% |
|
˜ 20% (limited information available) |
|
Ovary |
|
Homozygosity results in Nijmegen breakage syndrome-like disorder |
NBN (8q21) |
˜ 0.2% |
|
˜ 20% (limited information available) |
|
Ovary |
|
Homozygosity results in Nijmegen breakage syndrome |
MRE11A (11q21) |
˜ 0.1% |
|
˜ 30% (limited information available) |
|
Ovary |
|
Homozygosity results in Ataxia telangiectasia-like disorder |
MUTYH (1p34.1) |
˜ 0.1% |
|
˜ 10% (limited information available) |
|
Colon, small intestine |
|
Homozygosity results in MUTYH-associated polyposis |
