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Breast Cancer

November 03, 2017

Disease synonyms

Familial breast cancer, Breast cancer, Hereditary breast and ovarian cancer, HBOC, Familial male breast cancer


Inheritance pattern

Autosomal dominant


Clinical features

Breast cancer is the most common cancer among women and it is the third leading cause of cancer death 1. Approximately 1 in 8 women (12%) will develop breast cancer in their lifetime1. In year 2017, the estimated new cases and deaths were: 252,710 and 40,610 in USA. The risk factors include increasing age, inheritance susceptibility, alcohol intake, breast tissue density, estrogen, obesity, hormone etc.

Among several breast cancer risk genes, BRCA1 and BRCA2 are the most significant ones. Pathogenic variants in these two genes are asscociated with Hereditary breast and ovarian cancer (HBOC). HBOC should be suspected in individuals with a personal or family history of any of the following (based on the summarized data from Gene Reviews 1):

  • Breast cancer diagnosed at or before age 50 years
  • Ovarian cancer
  • Multiple primary breast cancers, in either one or both breasts
  • Male breast cancer
  • Triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative)
  • The combination of pancreatic cancer and/or prostate cancer with breast cancer, and/or ovarian cancer
  • Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
  • Two or more relatives with breast cancer (at least one under age 50)
  • Three or more relatives with breast cancer at any age
  • A previously identified BRCA1 or BRCA2 pathogenic variant in the family

Breast cancer and/or HBOC susceptibility is a complex phenomenon, in which multiple genes may play a role. An estimated 5-10% of all breast ovarian cancers are directly attributed to inherited gene variants in the BRCA1 and BRCA2 genes1. About 46-87% of women (BRCA1) and 38-84% (BRCA2) of women with variants will develop breast ovarian cancer during their lifetimes 2-8.

Genetic changes in other, non-BRCA genes, are rarer but can also contribute to the risk of breast ovarian cancer (see Figure 1). All genes associated with breast cancer, depending on their penetrance, can be classified into the following three groups 9, 10, 11 (Figure 1):

  • Highly penetrant genes, including BRCA1, BRCA2, RAD51C, NBN, TP53, STK11, PTEN
  • Moderately penetrant genes, including CHEK2, PALB2, BRIP1, ATM, RAD50
  • Low penetrant genes, including FGFR2, CYP1A1, XRCC3, XRCC1, MAP3K1, TOX3, TGFB1, LSP1

Figure 2. Contribution of pathogenic variants in non BRCA1/2 genes to familial breast cancer, according to the large genetic study on 2134 BRCA1/BRCA2 negative women with familial breast cancer 13. 


The genes described as high penetrance breast cancer susceptibility genes are typically tumor suppressor genes that participate in cellular proliferation and thus in tumor growth 12. Each HBOC-associated gene may have a relatively small effect on breast cancer risk; however, in combination with other genetic loci and/or environmental factors, variants of this kind might significantly alter breast cancer risk 1. Individuals with heterozygous variants in tumor suppressor genes have an increased breast cancer risk of between 1.5-5 1,3. The lifetime risks of BRIP1 and PALB2 variants are associated with a 20-50% lifetime risk of breast cancer 12. Female relatives of individuals with ATM or CHEK2 variants have a 2-4 fold increased risk of breast cancer 1, 12. Today’s powerful, novel tools for large-scale sequencing and genetic testing give us more information about the genetic basis of breast ovarian cancer and its association with numerous moderate risk genes, such as MSH2, MSH6, PMS1, PMS2, RAD50, RAD51C, RAD51D, and XRCC211, 12.


Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
ABRAXAS1 611143
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR
BARD1 601593 familial breast-ovarian cancer type 2 AD
BRCA1 113705 familial breast-ovarian cancer type 1; pancreatic cancer type 4; Fanconi anemia, complementation group S AD, AR
BRCA2 600185 familial breast-ovarian cancer type 2; Medulloblastoma; Prostate Cancer; Wilms tumor, type 1; Fanconi anemia complementation group D1; pancreatic cancer type 2 AD, AR
BRIP1 605882 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group J AD
CDH1 192090 familial breast-ovarian cancer type 2; blepharocheilodontic syndrome 1; Gastric Cancer, Hereditary Diffuse; Ovarian Cancer; Prostate Cancer; endometrial cancer AD
CHEK2 604373 familial breast-ovarian cancer type 2; Prostate Cancer; Osteogenic Sarcoma; Li-Fraumeni syndrome 2 AD
DICER1 606241 Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors; Rhabdomyosarcoma, embryonal, 2; Pleuropulmonary blastoma AD
EPCAM 185535 Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8 AR
FANCC 613899 Fanconi anemia of complementation group C AR
MEN1 613733 multiple endocrine neoplasia type 1 AD
MLH1 120436 Muir-Torre syndrome; mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-2 AD, AR
MRE11 600814 Ataxia-telangiectasia-like disorder type 1 AR
MSH2 609309 Lynch syndrome; Muir-Torre syndrome; mismatch repair cancer syndrome AD, AR
MSH6 600678 mismatch repair cancer syndrome; endometrial cancer; hereditary nonpolyposis colorectal cancer-5 AD, AR
MUTYH 604933 familial adenomatous polyposis type 2; Gastric Cancer AR
NBN 602667 Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia AR
PALB2 610355 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group N; Pancreatic cancer, susceptibility to, 3 AD
PMS1 600258
PMS2 600259 mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-4 AR
PTEN 601728 Cowden syndrome 1; Cowden syndrome type 2; Bannayan-Riley-Ruvalcaba syndrome; Prostate Cancer; Macrocephaly/autism syndrome; Meningioma, familial, susceptibility to AD
RAD50 604040 Nijmegen breakage syndrome-like disorder
RAD51C 602774 Fanconi anemia of complementation group O; Breast-ovarian cancer, familial, susceptibility to, 3 AR
RAD51D 602954 susceptibility to familial breast-ovarian cancer type 4
RECQL 600537
SMARCA4 603254 Rhabdoid tumor predisposition syndrome 2; mental retardation-16 AD
STK11 602216 Peutz-Jeghers syndrome; Pancreatic Cancer; Spermatocytic seminoma, somatic AD
TP53 191170 familial breast-ovarian cancer type 2; colorectal cancer; Hepatocellular Carcinoma; Glioma susceptibility 1; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD
XRCC2 600375 Fanconi anemia, complementation group U AR

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
ABRAXAS1 611143
APC 611731 colorectal cancer; Hepatocellular Carcinoma; Desmoid disease, hereditary; familial adenomatous polyposis; Gastric Cancer AD
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR
AXIN2 604025 colorectal cancer; oligodontia-colorectal cancer syndrome AD
BAP1 603089 Tumor predisposition syndrome AD
BARD1 601593 familial breast-ovarian cancer type 2 AD
BLM 604610 Bloom syndrome AR
BMPR1A 601299 Juvenile polyposis syndrome, infantile form AD
BRCA1 113705 familial breast-ovarian cancer type 1; pancreatic cancer type 4; Fanconi anemia, complementation group S AD, AR
BRCA2 600185 familial breast-ovarian cancer type 2; Medulloblastoma; Prostate Cancer; Wilms tumor, type 1; Fanconi anemia complementation group D1; pancreatic cancer type 2 AD, AR
BRIP1 605882 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group J AD
CDH1 192090 familial breast-ovarian cancer type 2; blepharocheilodontic syndrome 1; Gastric Cancer, Hereditary Diffuse; Ovarian Cancer; Prostate Cancer; endometrial cancer AD
CDK4 123829 Melanoma, Cutaneous Malignant, Susceptibility To, 3 AD
CDKN2A 600160 Malignant melanoma 2; Pancreatic cancer/melanoma syndrome AD
CHEK2 604373 familial breast-ovarian cancer type 2; Prostate Cancer; Osteogenic Sarcoma; Li-Fraumeni syndrome 2 AD
DICER1 606241 Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors; Rhabdomyosarcoma, embryonal, 2; Pleuropulmonary blastoma AD
DIS3L2 614184 Perlman syndrome AR
EPCAM 185535 Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8 AR
FANCC 613899 Fanconi anemia of complementation group C AR
FH 136850 Leiomyomatosis and renal cell cancer; Fumarase deficiency AD, AR
FLCN 607273 colorectal cancer; Birt-Hogg-Dube syndrome; Renal carcinoma, chromophobe, somatic; primary spontaneous pneumothorax AD
GALNT12 610290 Colorectal cancer, susceptibility to, 1
HNF1B 189907 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic AD
HOXB13 604607 Hereditary prostate cancer type 9
KIT 164920 Mast cell disease; Piebaldism; Spermatocytic seminoma, somatic; acute myeloid leukemia; gastrointestinal stromal tumor AD
MC1R 155555 oculocutaneous albinism type 2; skin/hair/eye pigmentation 2; Melanoma, cutaneous malignant, susceptibility to, 5 AR
MEN1 613733 multiple endocrine neoplasia type 1 AD
MET 164860 Hepatocellular Carcinoma; Renal cell carcinoma, papillary; deafness type 97 AD, AR
MITF 156845 Albinism, Ocular, With Sensorineural Deafness; Tietz Syndrome; Waardenburg syndrome type 2A; Melanoma, Cutaneous Malignant, Susceptibility To, 8 AD, AR
MLH1 120436 Muir-Torre syndrome; mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-2 AD, AR
MLH3 604395 colorectal cancer; endometrial cancer; Colorectal cancer, hereditary nonpolyposis, type 7 AD
MRE11 600814 Ataxia-telangiectasia-like disorder type 1 AR
MSH2 609309 Lynch syndrome; Muir-Torre syndrome; mismatch repair cancer syndrome AD, AR
MSH3 600887 endometrial cancer; Familial adenomatous polyposis 4 AR
MSH6 600678 mismatch repair cancer syndrome; endometrial cancer; hereditary nonpolyposis colorectal cancer-5 AD, AR
MUTYH 604933 familial adenomatous polyposis type 2; Gastric Cancer AR
NBN 602667 Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia AR
NF1 613113 neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Leukemia, juvenile myelomonocytic AD
NTHL1 602656 Familial adenomatous polyposis 3 AR
PALB2 610355 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group N; Pancreatic cancer, susceptibility to, 3 AD
PMS1 600258
PMS2 600259 mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-4 AR
POLD1 174761 Colorectal cancer, susceptibility to type 10; MANDIBULAR HYPOPLASIA, DEAFNESS, PROGEROID FEATURES, AND LIPODYSTROPHY SYNDROME AD
POLE 174762 Colorectal cancer, susceptibility to, 12; FILS syndrome AD, AR
POT1 606478 Melanoma, cutaneous malignant, susceptibility to, 10 AD
PRSS1 276000 hereditary pancreatitis AD
PTCH1 601309 Gorlin syndrome; Holoprosencephaly-7 AD
PTEN 601728 Cowden syndrome 1; Cowden syndrome type 2; Bannayan-Riley-Ruvalcaba syndrome; Prostate Cancer; Macrocephaly/autism syndrome; Meningioma, familial, susceptibility to AD
RAD50 604040 Nijmegen breakage syndrome-like disorder
RAD51C 602774 Fanconi anemia of complementation group O; Breast-ovarian cancer, familial, susceptibility to, 3 AR
RAD51D 602954 susceptibility to familial breast-ovarian cancer type 4
RECQL 600537
RET 164761 Hirschsprung disease; familial medullary thyroid carcinoma; multiple endocrine neoplasia 2B; pheochromocytoma; multiple endocrine neoplasia 2A; congenital central hypoventilation syndrome AD
RNF43 612482 AD
SDHA 600857 mitochondrial complex II deficiency; Leigh syndrome; dilated cardiomyopathy-1GG; paragangliomas type 5 AD, AR, M
SDHAF2 613019 paragangliomas type 2 AD
SDHB 185470 paragangliomas type 4; pheochromocytoma; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD
SDHC 602413 Paragangliomas 3; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD
SDHD 602690 paragangliomas 1; pheochromocytoma; mitochondrial complex II deficiency; paraganglioma and gastric stromal sarcoma AD, AR
SMAD4 600993 Myhre syndrome; Juvenile polyposis syndrome, infantile form; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Pancreatic Cancer AD
SMARCA4 603254 Rhabdoid tumor predisposition syndrome 2; mental retardation-16 AD
STK11 602216 Peutz-Jeghers syndrome; Pancreatic Cancer; Spermatocytic seminoma, somatic AD
TGFBR2 190182 Esophageal cancer, somatic; Loeys-Dietz syndrome 2; Colorectal cancer, hereditary nonpolyposis, type 6 AD
TP53 191170 familial breast-ovarian cancer type 2; colorectal cancer; Hepatocellular Carcinoma; Glioma susceptibility 1; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD
TSC1 605284 tuberous sclerosis type 1 AD
TSC2 191092 tuberous sclerosis-2 AD
VHL 608537 Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 AD, AR
WT1 607102 Frasier syndrome; Mesothelioma, somatic; Wilms tumor, type 1; Denys-Drash syndrome; Nephrotic syndrome, type 4; Meacham syndrome AD
XRCC2 600375 Fanconi anemia, complementation group U AR
XRCC3 600675 familial breast-ovarian cancer type 2 AD

Different testing options

Genetic testing of breast cancer-related genes may confirm a diagnosis of breast cancer and can help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. Early diagnostics of breast and/or ovarian cancer can increase the chances of detecting and localizing the cancer before it spreads. Furthermore, improvements in early detection and treatment of breast cancer have led to longer survival of breast cancer patients 1, 15. CENTOGENE has designed a special set of breast cancer related panels, specifically design to fit the affected family or individual with a family history of breast cancer.

The BRCA1/BRCA2 panel is designed for individuals with family history of breast/ovarian cancer with a previously identified pathogenic variant in the BRCA1 or BRCA2 genes. This panel includes MGS sequencing methods for the most common BRCA1/BRCA2 pathogenic single nucleotide variants as well as MLPA analysis for large deletion/duplications.

CENTOGENE has also designed the CentoBreast® panel, a comprehensive panel intended for genetic testing of hereditary breast-ovarian cancers caused by variants in those genes most commonly associated with breast-ovarian cancer. Using NGS bidirectional sequencing of the genes in the panel, including all exons, exon/intron boundaries and promoter regions, with additional validation of the sequencing results for every detected genetic variant, we can provide 100% variant detection reproducibility for Sanger sequencing.

The CentoBreast® panel includes all high and moderate risk genes associated with HBOC. Genetic testing for breast ovarian cancer improves our chances of preventing and treating at-risk individuals, enabling patients to reduce their cancer risk. It can give them a sense of relief regarding their future risk of cancer or allow them to participate in medical research that could, in the long run, help reduce deaths from hereditary breast and ovarian cancer.

National Comprehensive Cancer Network guidelines 15 suggest that women with a BRCA1/2 pathogenic variant, or other breast cancer-causing pathogenic variants, may wish to consider bilateral mastectomy as a primary surgical treatment of breast cancer because of their elevated rate of ipsilateral and contralateral breast cancer. Treatment of ovarian and other cancers in individuals with pathogenic variants in BRCA1/2 and other genes associated with breast cancer is similar to that of sporadic cancers.

For individuals affected with breast/ovarian cancer, a team of specialist, will discuss the treatment options and possible side effects. Common treatment options include surgery, radiation and chemotherapy, and hormone therapy. Every step of the therapy must be carefully planned, based on the personal medical history and conditions.



Differential diagnosis

The differential diagnosis of breast cancer -related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Fibroadenomas and cysts of breasts and ovarian benign cysts)
  • Breast lymphoma, and/or metastasis from other primary sites
  • Chronic or acute mastitis and other inflammatory cysts in breasts
  • Papilloma, ductal carcinoma, duct ectasia, and fibrocystic disease
  • Traumatic fat necrosis
  • Hyalinized fibroadenoma.

Referral reasons

BRCA1/BRCA2-associated breast cancer panel testing is recommended for those individuals who have one of the following 1, 15:

  • A family member with a BRCA1/BRCA2 gene pathogenic variant
  • A personal history of breast cancer at age 45 or younger
  • A personal history of breast cancer at any age and a family member diagnosed with breast cancer at age 50 or younger
  • A personal history of breast cancer at any age and two or more family members diagnosed with breast, pancreatic and/or aggressive prostate cancer at any age
  • Ashkenazi Jewish heritage and a personal history of breast or pancreatic cancer
  • A personal history of triple negative breast cancer diagnosed at age 60 or younger
  • A personal or family history of ovarian cancer
  • A personal or family history of male breast cancer
  • A family member diagnosed with breast cancer at age 45 or younger

NCCN guidelines 15 recommend referral to a genetics expert (including Breast ovarian cancer panel, Breast ovarian cancer panel PLUS and CentoBreast®) for evaluation of breast cancer patients if they meet any of these criteria:

  • Anyone with a family history of one or more of the following:
    • A blood relative with a known variants in a gene which increases cancer risk
    • A blood relative with two or more primary breast cancers
    • Two or more relatives with breast cancer on the same side of the family, at least one who was diagnosed before age 50
    • A blood relative with ovarian cancer
    • A close blood relative with breast cancer before age 45
    • A blood relative with male breast cancer

  • Anyone of Ashkenazi Jewish ancestry with breast, ovarian, or pancreatic cancer at any age
  • Anyone with a cancer diagnosis and one or more of the following:
    • A blood relative with a known variants in a gene which increases cancer risk
    • Breast cancer at or before the age of 50
    • Triple-negative breast cancer at or before the age of 60
    • Ovarian, fallopian tube, or primary peritoneal cancer at any age
    • Male breast cancer at any age

  • Anyone with breast cancer at any age and one or more of the following:
    • A blood relative with a known variants in a gene which increases cancer risk
    • An primary breast cancer

  • Anyone with a personal or family history of three or more of the following, especially if any of the cases are diagnosed before age 50:
    • Pancreatic cancer
    • Prostate cancer
    • Melanoma
    • Sarcoma
    • Adrenal cancer
    • Brain tumors
    • Leukemia
    • Uterine cancer
    • Thyroid cancer
    • Kidney cancer
    • Diffuse gastric cancer
    • Colon cancer.


Test utility

Genetic testing with CENTOGENE breast cancer associated panels can contribute to an early diagnosis, improved choice of treatment, and genetic counselling for family members. At CENTOGENE we have analyzed thousands of breast-ovarian cancer patients samples from all over the world. This medical expertise, combined with the constant optimization of our internal processes and implementation of new diagnostic techniques, allows us to support you with attractive new diagnostics offers for genetic testing for breast/ovarian cancers.

Sequencing, deletion/duplication of breast cancer related genes should be performed in all individuals suspected of having breast cancer. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes. Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of breast/ovarian cancer, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.