BRCA2 (breast cancer 2, early onset)

2010-03-01   Frédéric Guénard , Francine Durocher 

Cancer Genomics Laboratory, Oncology, Molecular Endocrinology Research Centre, CRCHUL, CHUQ, Laval University, Quebec, G1V 4G2, Canada





The BRCA2 gene is composed of 27 exons and spans approximately 84.2 kb of genomic DNA.


The BRCA2 gene encodes a 11386 bp mRNA transcript. Transcription site is located 227 bp upstream the first ATG of the BRCA2 ORF. The translation start site is located in exon 2.


No pseudogene reported.


Atlas Image
Structure of BRCA2. BRCA2 is a 3418 aa protein. BRC repeats: BRCA C-terminal repeats; NLS: Nuclear localization signals.


Human BRCA2 protein is composed of 3418 amino acids (384 kDa).
The N-terminal part of the BRCA2 protein contains a transcriptional activation domain (aa 18-105).
BRCA2 exon 11 encodes eight conserved motifs termed BRC repeats. Each of these repeats is composed of about 30 residues.
A DNA-binding domain has been located in the C-terminal region of the BRCA2 protein (aa 2478-3185). It is composed of a conserved helical domain and three OB folds.
Two nuclear localization signals (NLS) have been identified in the C-terminal region of BRCA2.


BRCA2 expression is proportional to the rate of cell proliferation. Non-dividing cells do not express BRCA2 while wide expression of BRCA2 was observed in actively dividing tissues, including the epithelium of the breast during puberty and pregnancy.
The BRCA2 expression is regulated during the cell cycle, with highest expression during the S phase of the cell cycle.
Most of the BRCA2 proteins are associated to DSS1. The presence of DSS1 was demonstrated to stabilize the BRCA2 protein.


BRCA2 is a nuclear protein.


BRCA2 has been implicated in maintenance of genomic integrity and in the cellular response to DNA damage. The BRCA2 protein interacts with the RAD51 recombinase to regulate homologous recombination (HR). BRCA2 regulates the intracellular localization of RAD51. It also targets the RAD51 to ssDNA and inhibits dsDNA binding, thus regulating/enhancing DNA strand exchange activity of RAD51. CHEK1 and CHEK2 both phosphorylate the RAD51/BRCA2 complex and regulate the functional association of this complex in response to DNA damage.
BRCA2 is also implicated in cell cycle checkpoints. Following exposure to X-rays or UV light, cells expressing truncated BRCA2 protein exhibit arrest in the G1 and G2/M phases. BRCA2 protein plays a role in mitotic spindle assembly checkpoints through modulation of the level of spindle assembly checkpoint proteins including Aurora A and Aurora B.
A role in regulation of transcription has been attributed to BRCA2. BRCA2 binding to the DSS1 protein appears to be required for proper completion of cell division in yeast.
The BRCA2 protein demonstrated the ability to stimulate transcription. For example, exogenous expression of BRCA2 can stimulate transcription of androgen receptor-regulated genes. This function of BRCA2 is regulated by the binding of the EMSY protein to the region of BRCA2 responsible for transcriptional activation. An excess of EMSY results in silencing of BRCA2-driven transcriptional activation.
BRCA2 localizes to meiotic chromosomes during early meiotic prophase I when homologous chromosomes undergo synapsis. Moreover, BRCA2 interacts with the meiosis-specific recombinase DMC1, thus implicating BRCA2 in meiotic recombination.


BRCA2 homologs have been found in a diverse range of organisms. In addition to zebrafish and C. elegans, homologs exist in diverse eukaryotes, from plants to parasitic organisms.
Low general conservation is found in BRCA2. Higher level of homology is observed for several segments, including transactivation domain, BRC repeats and nuclear localization signals located within C-terminal region.



High risk of breast and ovarian cancer is associated with germline BRCA2 mutations. Cumulative risk of breast cancer in BRCA2 mutation carriers was estimated to 45% by the age of 70 years while ovarian cancer risk in carriers was estimated to 11%. Increased risk of several other cancers are associated with BRCA2 mutations, especially for prostate and pancreatic cancer.


Somatic mutations in BRCA2 are infrequent in sporadic breast cancer. Methylation of the BRCA2 promoter has not been detected in normal tissues nor in breast and ovarian cancers. Loss of heterozygosity at the BRCA2 locus has been frequently found in sporadic breast and ovarian tumors.

Implicated in

Entity name
Breast cancer
Informations regarding breast cancer and BRCA2 mutations and polymorphisms are available in a central repository formed by the National Human Genome Research; National Institute of Health. This repository, named Breast Cancer Information Core (BIC) - NHGRI, is available at the following address:
Breast tumors in BRCA2 carriers are found at higher histologic grade (2 and 3) than sporadic tumors. Tumors from BRCA2 carriers are more commonly found to be stage IV than sporadic control tumors and BRCA2-associated breast cancer cases are more often node-positive than control breast cancer cases.
BRCA2 mutation carriers show younger mean age at diagnosis than sporadic breast cancer cases. Bilateral breast cancer is found more commonly in BRCA2-associated breast cancer than in sporadic breast cancer.
ER and PR expression in BRCA2 tumors are similar than in control tumors, which contrasts with ER and PR expression found in BRCA1 tumors.
It was suggested that genomic rearrangements account for 7.7% of the BRCA2 mutation spectrum. Loss of the wild-type allele is not required for breast tumorigenesis in BRCA2 mutation carriers.
Somatic mutations of the BRCA2 gene are an infrequent event in sporadic breast cancer tumors. Loss of heterozygosity at the BRCA2 locus on chromosome 13q12-q13 was observed in approximately 30% of sporadic breast cancer. Methylation of the CpG dinucleotide within the BRCA2 promoter is not found in normal and neoplastic breast tissues.
Entity name
Male breast cancer
A cumulative risk of 6% and 7% of developing breast cancer by the age of 70 and 80, respectively, has been estimated for male BRCA2 mutation carriers. BRCA2 mutations have been found in 14% of familial male breast cancer and 4% of unselected male breast cancer cases.
Male breast cancers are mostly ductal or unclassified carcinomas. Papillary, mucinous and lobular carcinomas each represent less than 3% of male breast cancers. Estrogen receptor and progesterone receptor expression is found in approximately 90% and 81% of male breast cancers, respectively.
Overall survival rates for male breast cancers are lower than for female breast cancers due to the older age and more advances disease at the time of diagnosis. Male breast cancers associated with BRCA2 mutation are diagnosed at younger age than sporadic male breast cancer cases.
Entity name
Ovarian cancer
Carriers of mutations in the central portion of BRCA2, termed OCCR (ovarian cancer cluster region; aa 1012-2210), are at higher risk of ovarian cancer and lower breast cancer risk than carriers of mutations outside the OCCR.
Ovarian cancer is mostly epithelial tumors (90%) and lifetime risk of ovarian cancer in the general population is estimated to be 1-1.5%. Risk of ovarian cancer in BRCA2 mutation carriers is estimated to be 10%.
BRCA2 ovarian tumors are similar to BRCA1 ovarian tumors as these two types of tumors are more likely to be serous adenocarcinomas and higher grade than control tumors. BRCA2-associated ovarian cancers occur later in life than BRCA1-related or control ovarian tumors.
Complete loss of the wild-type BRCA2-allele is observed in BRCA2-associated ovarian cancers. Loss of heterozygosity at 13q12-q14 is also observed in sporadic epithelial ovarian tumors. On the other hand, CpG dinucleotide methylation of the BRCA2 promoter is not found in sporadic ovarian cancers.
Entity name
Prostate cancer
Different studies conducted on BRCA2 mutation carriers revealed an increased risk of prostate cancer in BRCA2 mutation carriers. Relative risk associated with BRCA2 mutations is estimated to be approximately 2.5 to 5.
Protein-truncating BRCA2 mutations are associated with early-onset prostate cancer. Different studies revealed that BRCA2 mutations are responsible for less than 1% of early-onset prostate cancer in the US Caucasian population while such mutations are responsible for 2.3% of early-onset prostate cancer diagnosed in United Kingdom.
Most studies conducted on hereditary prostate cancer families did not revealed a contribution of BRCA2 truncating mutations in these families. However, a small study conducted on a limited number of families found BRCA2 mutations in two families. Incomplete segregation of the mutation with the disease was found in these families as affected brothers did not carry these mutations.
BRCA2 mutation carriers have a significantly lower mean age at diagnosis of prostate cancer and shorter mean survival time than non-carriers. BRCA2 mutation carriers show more advanced tumor stage and higher grade at diagnosis. Prostate cancer carriers of a BRCA2 mutation show poorer survival than BRCA1 carriers. Prostate cancer patients which are carriers of the 999del5 Icelandic founder mutation appear to have worse prognosis than non-carriers of this mutation.
Histopathological features of prostate cancer in BRCA2 mutation carriers revealed that prostate cancer developed in mutation carriers show higher Gleason scores in than non-carriers.
Allelic loss at the BRCA2 locus was identified in a majority of prostate tumor samples from carriers of the c.999del5 mutation, thus suggesting that no functional BRCA2 protein is found in these tumors.
Entity name
Stomach cancer
Stomach cancer was reported in family members of women with ovarian cancer carrying a BRCA2 mutation within the OCCR. On the other hand, the presence of stomach cancer in relatives of ovarian cancer cases is strongly predictive of the presence of a BRCA2 mutation. Specifically, the BRCA2 999del5 mutation is associated with an increased risk of stomach cancer in first- and second-degree relatives.
Assessment of the presence of non-breast or ovarian cancers in BRCA2 mutation carriers estimated a relative risk of stomach cancer of 2.59 to be associated with BRCA2 mutations. Meta-analysis of published studies latter confirmed increased risk of stomach cancer in BRCA2 carriers.
Entity name
Pharyngeal cancer
An increased risk of buccal cavity and pharynx cancer was suggested during the assessment of cancers other than breast and ovarian cancer in BRCA2 mutation carriers. This was thereafter confirmed in a cohort of BRCA2 mutation carriers leading to the estimation of a relative risk of 7.3 (95% CI = 2.0 - 18.6). Higher relative risk of pharyngeal cancer is found for carriers younger than 65 years old.
Entity name
Gallbladder and bile duct cancer
Evaluation of risks of cancers other than breast and ovarian cancers in BRCA2 carriers found a higher risk of gallbladder and bile duct cancer in BRCA2 carriers (RR = 4.97; 95% CI = 1.50-16.52). Specifically, the 6167delT Jewish Ashkenazi founder BRCA2 mutation was observed at significantly higher rate in bile duct cancer cases than in population controls.
Entity name
Colon cancer
It was reported that risk of colorectal cancer in first-degree relatives of BRCA2 mutation carriers affected with ovarian cancer is increased by threefold for BRCA2 mutations located within the OCCR.
Analysis of a BRCA2 mutation in different families led to the suggestion that BRCA2 mutations predispose to colon cancer. It was thereafter reported that BRCA2 mutation carriers are at increased risk of colon cancer before the age of 65 years old. The association of BRCA2 mutations with colon cancer was latter confirmed in a meta-analysis.
Entity name
Pancreas cancer
Different studies suggested that BRCA2 mutations are associated with less than 1% of sporadic pancreatic cancer in Caucasians while such mutations could account for 10% of sporadic pancreatic cancer in Ashkenazi Jewish population.
Approximately 10% of patients developing pancreatic cancer show patterns of hereditary predisposition. Screening of BRCA2 mutations in familial pancreatic cancer cases suggested that BRCA2 mutations account for 6-17% of these families. Following the identification of germline BRCA2 mutations in pancreatic cancer, it was evaluated that BRCA2 mutations confer roughly a 3.5-folds increased risk. Relative risk of pancreatic cancer was found to be higher at younger age (younger than 65 years old). Different studies evaluated the lifetime risk of pancreatic cancer in BRCA2 mutation carriers to be approximately 5%.
Among human malignancies, pancreatic cancer has one of the worst prognoses.
Pancreatic intraepithelial neoplasia (PanIN) analysis in BRCA2 mutation carriers revealed that loss of the wild type BRCA2 allele is found solely in high-grade PanIN, thus suggesting that biallelic inactivation of the BRCA2 gene is a late event in pancreatic tumorigenesis in patients with germline BRCA2 mutation.
Entity name
Malignant melanoma
BRCA2 mutation carriers were estimated to be at higher risk of developing malignant melanoma (RR = 2.58; 95% CI = 1.28-5.17). Despite many studies reported malignant melanoma in mutation carriers or in their relatives, other studies did not confirm this association.
Entity name
Bone cancer
An excess risk of bone cancer (RR = 14.4; 95% CI = 2.9 - 42.1) was observed in a cohort of BRCA2 mutation carriers from the Netherlands.
Entity name
Fanconi anemia (complementation group D1)
Biallelic mutations of the BRCA2 gene are responsible for Fanconi anemia subgroup D1 (FA-D1).
Fanconi anemia (FA) is a rare recessive disease characterized by various clinical features. Many developmental defects are found in FA patients. Radial aplasia, microcephaly, microphthalmia, small stature, skin hyperpigmentation and malformation of the kidneys are encountered in FA patients. Very high frequency of bone marrow failure, leukemia and squamous cell carcinoma of the head and neck as well as gynecological squamous cell carcinoma are associated with FA. Bone marrow failure generally leads to aplastic anemia during the first decade of life. Esophageal carcinoma and liver, brain, skin and renal tumors are also found in FA patients.
The FA-D1 and FA-N subgroups are clinically different from other FA subgroups as these subgroups are associated with increased predisposition to solid childhood malignancies such as medulloblastoma and Wilms tumor.
At the cellular level, FA is a chromosomal fragility syndrome. FA cells are hypersensitive to DNA interstrand crosslinking agents such as mitomycin C, diepoxybutane and cisplatin. In addition to hypersensitivity to these agents, FA cells show an increased number of spontaneous breaks.


Pubmed IDLast YearTitleAuthors
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107930872000BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications.Goggins M et al
89680851996Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.Goggins M et al
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125691432003BRCA2 germline mutations in familial pancreatic carcinoma.Hahn SA et al
146709282004Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.Hirsch B et al
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146518452003EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.Hughes-Davies L et al
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146472102003A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer.Jakubowska A et al
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124088342002BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis.Kojic M et al
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86402351996BRCA2 mutations in primary breast and ovarian cancers.Lancaster JM et al
162056302006DSS1 is required for the stability of BRCA2.Li J et al
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108996492000Prognosis and clinical presentation of BRCA2-associated breast cancer.Loman N et al
97816551998Pathobiologic characteristics of hereditary breast cancer.Lynch BJ et al
86230611996Familial pancreatic cancer: a review.Lynch HT et al
112073652001A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression.Marmorstein LY et al
103735121999Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals.Marston NJ et al
157981992005RAD-51-dependent and -independent roles of a Caenorhabditis elegans BRCA2-related protein during DNA double-strand break repair.Martin JS et al
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92424361997Characterization of the rat and mouse homologues of the BRCA2 breast cancer susceptibility gene.McAllister KA et al
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181829942008Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype.Mitra A et al
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112394552001BRCA2 is required for homology-directed repair of chromosomal breaks.Moynahan ME et al
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Other Information

Locus ID:

NCBI: 675
MIM: 600185
HGNC: 1101
Ensembl: ENSG00000139618


dbSNP: 675
ClinVar: 675
TCGA: ENSG00000139618


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Pancreatic cancerKEGGko05212
Homologous recombinationKEGGhsa03440
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
Cell CycleREACTOMER-HSA-1640170
Meiotic recombinationREACTOMER-HSA-912446
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
195536412009Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.1126
126775582003Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.777
126775582003Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.777
206094672010Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.564
145764342003Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.529
145764342003Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.529
206094682010Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.447
174168532007Meta-analysis of BRCA1 and BRCA2 penetrance.420
215656122011Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11.414
227895422012A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2.338


Frédéric Guénard ; Francine Durocher

BRCA2 (breast cancer 2, early onset)

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: