BRCA2 (breast cancer 2, early onset)

2010-03-01 Frédéric Guénard , Francine Durocher Affiliation

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

Identity

HGNC

BRCA2

LOCATION

13q13.1

LOCUSID

675

ALIAS

BRCC2,BROVCA2,FACD,FAD,FAD1,FANCD,FANCD1,GLM3,PNCA2,XRCC11

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

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

Transcription

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.

Pseudogene

No pseudogene reported.

Proteins

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

Description

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.

Expression

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.

Localisation

BRCA2 is a nuclear protein.

Function

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.

Homology

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.

Mutations

Germinal

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

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

Note

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: http://research.nhgri.nih.gov/bic/.

Disease

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.

Prognosis

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.

Oncogenesis

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

Note

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.

Disease

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.

Prognosis

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

Note

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.

Disease

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%.

Prognosis

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.

Oncogenesis

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

Note

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.

Prognosis

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.

Oncogenesis

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

Note

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

Note

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

Note

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

Note

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

Note

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%.

Prognosis

Among human malignancies, pancreatic cancer has one of the worst prognoses.

Oncogenesis

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

Note

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

Note

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)

Note

Biallelic mutations of the BRCA2 gene are responsible for Fanconi anemia subgroup D1 (FA-D1).

Disease

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.

Prognosis

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.

Cytogenetics

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
17700570	2007	Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer.	Agalliu I et al
9497100	1998	Inherited BRCA2 mutation associated with high grade breast cancer.	Agnarsson BA et al
12518367	2003	Cancer in Fanconi anemia, 1927-2001.	Alter BP et al
12677558	2003	Average 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.	Antoniou A et al
10213514	1999	Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study.	Armes JE et al
18317453	2008	The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage.	Bahassi EM et al
8758903	1996	A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.	Berman DB et al
9407955	1997	Nuclear location and cell cycle regulation of the BRCA2 protein.	Bertwistle D et al
9002670	1997	The BRC repeats are conserved in mammalian BRCA2 proteins.	Bignell G et al
8673099	1996	Internal repeats in the BRCA2 protein sequence.	Bork P et al
17052168	2006	Cellular functions of the BRCA tumour-suppressor proteins.	Boulton SJ et al
19303847	2009	The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51.	Carreira A et al
16950820	2006	The contribution of germline rearrangements to the spectrum of BRCA2 mutations.	Casilli F et al
10551859	1999	Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control.	Chen CF et al
9774970	1998	Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.	Chen J et al
9560268	1998	The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment.	Chen PL et al
10819533	1998	Expression of BRCA1 and BRCA2 in normal and neoplastic cells.	Chodosh LA et al
7577475	1995	Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13.	Cleton-Jansen AM et al
9365162	1997	Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers.	Collins N et al
8673091	1996	BRCA2 germline mutations in male breast cancer cases and breast cancer families.	Couch FJ et al
17301269	2007	The prevalence of BRCA2 mutations in familial pancreatic cancer.	Couch FJ et al
15375219	2004	Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2.	Daniels MJ et al
11239456	2001	Role of BRCA2 in control of the RAD51 recombination and DNA repair protein.	Davies AA et al
8610268	1996	Breast cancer in men.	Donegan WL et al
9245992	1997	Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13.	Easton DF et al
12474142	2003	Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene.	Edwards SM et al
17515904	2007	Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2.	Esashi F et al
11207041	2001	The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel.	Figer A et al
9497246	1998	Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.	Ford D et al
16369438	2005	BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian.	Friedenson B et al
9012404	1997	Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.	Friedman LS et al
10969800	2000	The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.	Gayther SA et al
15221988	2004	Breast carcinoma in men: a population-based study.	Giordano SH et al
14569130	2003	A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology.	Giusti RM et al
10793087	2000	BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications.	Goggins M et al
8968085	1996	Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.	Goggins M et al
11550149	2001	Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors.	Gras E et al
12569143	2003	BRCA2 germline mutations in familial pancreatic carcinoma.	Hahn SA et al
14670928	2004	Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.	Hirsch B et al
12065746	2002	Biallelic inactivation of BRCA2 in Fanconi anemia.	Howlett NG et al
14651845	2003	EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.	Hughes-Davies L et al
18047734	2007	The Fanconi anemia pathway and ubiquitin.	Jacquemont C et al
14647210	2003	A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer.	Jakubowska A et al
17597348	2007	Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis.	King TA et al
12408834	2002	BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis.	Kojic M et al
12393516	2003	A 20-year perspective on the International Fanconi Anemia Registry (IFAR).	Kutler DI et al
15073127	2004	Pathology of ovarian cancers in BRCA1 and BRCA2 carriers.	Lakhani SR et al
8640235	1996	BRCA2 mutations in primary breast and ovarian cancers.	Lancaster JM et al
16205630	2006	DSS1 is required for the stability of BRCA2.	Li J et al
12967658	2003	Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer.	Lo T et al
10899649	2000	Prognosis and clinical presentation of BRCA2-associated breast cancer.	Loman N et al
9781655	1998	Pathobiologic characteristics of hereditary breast cancer.	Lynch BJ et al
8623061	1996	Familial pancreatic cancer: a review.	Lynch HT et al
11207365	2001	A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression.	Marmorstein LY et al
10373512	1999	Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals.	Marston NJ et al
15798199	2005	RAD-51-dependent and -independent roles of a Caenorhabditis elegans BRCA2-related protein during DNA double-strand break repair.	Martin JS et al
16998502	2006	Fanconi anaemia genes and susceptibility to cancer.	Mathew CG et al
9242436	1997	Characterization of the rat and mouse homologues of the BRCA2 breast cancer susceptibility gene.	McAllister KA et al
9126734	1997	Transcriptional activation functions in BRCA2.	Milner J et al
18182994	2008	Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype.	Mitra A et al
9192668	1997	RAB22 and RAB163/mouse BRCA2: proteins that specifically interact with the RAD51 protein.	Mizuta R et al
11239455	2001	BRCA2 is required for homology-directed repair of chromosomal breaks.	Moynahan ME et al
12097290	2002	Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.	Murphy KM et al
15343273	2004	BRCA1 and BRCA2: 1994 and beyond.	Narod SA et al
18577985	2008	Rapid progression of prostate cancer in men with a BRCA2 mutation.	Narod SA et al
14559878	2003	Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.	Offit K et al
9140390	1997	Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients.	Ozçelik H et al
14506147	2003	Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers.	Palacios J et al
17767707	2007	Association between the BRCA2 N372H variant and male breast cancer risk: a population-based case-control study in Tuscany, Central Italy.	Palli D et al
9660919	1998	Involvement of Brca2 in DNA repair.	Patel KJ et al
12442171	2002	Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.	Pellegrini L et al
9133444	1997	Developmental expression of Brca2 colocalizes with Brca1 and is associated with proliferation and differentiation in multiple tissues.	Rajan JV et al
15689453	2005	Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour.	Reid S et al
11179017	2001	Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.	Risch HA et al
12393424	2003	Cancer incidence in persons with Fanconi anemia.	Rosenberg PS et al
11100717	2000	In search of the tumour-suppressor functions of BRCA1 and BRCA2.	Scully R et al
9126738	1997	Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2.	Sharan SK et al
12756300	2003	BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription.	Shin S et al
19628690	2009	The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange.	Shivji MK et al
15014444	2004	Brca2 is involved in meiosis in Arabidopsis thaliana as suggested by its interaction with Dmc1.	Siaud N et al
9383000	1997	BRCA2 mutation in Icelandic prostate cancer patients.	Sigurdsson S et al
10728701	2000	BRCA1 and BRCA2 have a limited role in familial prostate cancer.	Sinclair CS et al
10570174	1999	Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.	Spain BH et al
11850831	2002	Conserved domains in the chicken homologue of BRCA2.	Takata M et al
16493006	2006	Molecular pathogenesis of Fanconi anemia: recent progress.	Taniguchi T et al
8589730	1996	The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.	Tavtigian SV et al
8640236	1996	Low incidence of BRCA2 mutations in breast carcinoma and other cancers.	Teng DH et al
11170890	2001	Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.	Thompson D et al
8673089	1996	A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.	Thorlacius S et al
17541404	2007	Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1.	Thorslund T et al
17565157	2007	Prostate cancer progression and survival in BRCA2 mutation carriers.	Tryggvadóttir L et al
12114473	2002	The effect of a single BRCA2 mutation on cancer in Iceland.	Tulinius H et al
11832208	2002	Cancer susceptibility and the functions of BRCA1 and BRCA2.	Venkitaraman AR et al
10550133	1999	Survival in hereditary breast cancer associated with germline mutations of BRCA2.	Verhoog LC et al
15070707	2004	Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia.	Wagner JE et al
11929857	2002	Structural analysis of the chicken BRCA2 gene facilitates identification of functional domains and disease causing mutations.	Warren M et al
9405383	1997	RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2.	Wong AK et al
8524414	1995	Identification of the breast cancer susceptibility gene BRCA2.	Wooster R et al
8091231	1994	Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.	Wooster R et al
12228710	2002	BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.	Yang H et al
10837032	2000	Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation.	Yu VP et al
9491884	1998	BRCA1, BRCA2, and DNA damage response: collision or collusion?	Zhang H et al
10433620	1999	Cancer risks in BRCA2 mutation carriers.
16141007	2005	Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.	van Asperen CJ et al

Other Information

Locus ID:

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

Variants:

dbSNP: 675
ClinVar: 675
TCGA: ENSG00000139618
COSMIC: BRCA2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000139618	ENST00000380152	P51587
ENSG00000139618	ENST00000470094	H0YE37
ENSG00000139618	ENST00000528762	H0YD86
ENSG00000139618	ENST00000530893	A0A590UJI7
ENSG00000139618	ENST00000544455	P51587
ENSG00000139618	ENST00000665585	A0A590UJU6
ENSG00000139618	ENST00000666593	A0A590UJ24
ENSG00000139618	ENST00000670614	Q8IU64
ENSG00000139618	ENST00000671466	Q8IU64

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Homologous recombination	KEGG	ko03440
Pancreatic cancer	KEGG	ko05212
Homologous recombination	KEGG	hsa03440
Pathways in cancer	KEGG	hsa05200
Pancreatic cancer	KEGG	hsa05212
Fanconi anemia pathway	KEGG	ko03460
Fanconi anemia pathway	KEGG	hsa03460
Cell Cycle	REACTOME	R-HSA-1640170
Meiosis	REACTOME	R-HSA-1500620
Meiotic recombination	REACTOME	R-HSA-912446
DNA Repair	REACTOME	R-HSA-73894
DNA Double-Strand Break Repair	REACTOME	R-HSA-5693532
Homology Directed Repair	REACTOME	R-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)	REACTOME	R-HSA-5693567
HDR through Homologous Recombination (HRR)	REACTOME	R-HSA-5685942
Homologous DNA Pairing and Strand Exchange	REACTOME	R-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchange	REACTOME	R-HSA-5693616
Resolution of D-Loop Structures	REACTOME	R-HSA-5693537
Resolution of D-loop Structures through Holliday Junction Intermediates	REACTOME	R-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	REACTOME	R-HSA-5693554
Breast cancer	KEGG	ko05224
Breast cancer	KEGG	hsa05224

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association
PA164920420	olaparib	Chemical	LabelAnnotation	associated
PA166131610	niraparib	Chemical	LabelAnnotation	associated
PA166163418	rucaparib	Chemical	LabelAnnotation	associated
PA166182740	talazoparib	Chemical	LabelAnnotation	associated

References

Pubmed ID	Year	Title	Citations
37488236	2024	Functional annotation of variants of the BRCA2 gene via locally haploid human pluripotent stem cells.	3
37657917	2024	Recurrent BRCA2 exon 3 deletion in Assyrian families.	0
37714298	2024	BRCA1/2 Haploinsufficiency: Exploring the Impact of Losing one Allele.	1
37833038	2024	Subset of retinoblastoma tumours is associated with BRCA1/2 mutations.	0
37850614	2024	Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.	3
37934606	2024	PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation.	0
38030749	2024	Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis.	1
38057686	2024	Presence of crown-like structures in breast adipose tissue; differences between healthy controls, BRCA1/2 gene mutation carriers and breast cancer patients.	0
38167124	2024	BRCA1 and BRCA2 germline mutations in Chinese Hakka breast cancer patients.	0
38171988	2024	Beyond BRCA: Diagnosis and management of homologous recombination repair deficient pancreatic cancer.	0
38244544	2024	BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair.	8
38244928	2024	Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.	4
38300310	2024	Reclassifying BRCA1 c.4358-2A > G and BRCA2 c.475 + 5G > C variants from "Uncertain Significance" to "Pathogenic" based on minigene assays and clinical evidence.	0
38308422	2024	BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer.	2
38365640	2024	Central nervous system metastases in breast cancer patients with germline BRCA pathogenic variants compared to non-carriers: a matched-pair analysis.	0

Citation

Frédéric Guénard ; Francine Durocher

BRCA2 (breast cancer 2, early onset)

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: http://atlasgeneticsoncology.org/gene/164/deep-insight-explorer/js/lib/favicon/manifest.json