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BRCA1
BRCA1 DNA repair associated
The BRCA1 gene provides instructions for a protein critical in DNA repair and cell growth regulation, acting as a tumour suppressor to prevent uncontrolled cell division. Mutations in BRCA1 are well-established risk factors for hereditary breast and ovarian cancer syndrome, significantly increasing an individual's likelihood of developing certain cancers.
BRCA1 is located on the long (q) arm of chromosome 17, at band 17q21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The BRCA1 (BRCA1 DNA repair associated) gene encodes a protein that primarily functions as a tumour suppressor. This protein is crucial for managing cellular responses to DNA damage, a process vital for preventing uncontrolled cell proliferation. When the BRCA1 protein is functional, it aids in repairing breaks within DNA, thereby preserving the stability and integrity of the cell's genetic material. Its role also extends to regulating the activity of other genes and contributing to embryonic development.
Inherited changes, or pathogenic variants, in the BRCA1 gene are strongly linked to an elevated risk of developing specific cancers, most notably breast and ovarian cancers. These germline mutations are present in every cell of the body and can be passed down through generations, explaining why these cancers often cluster within families. While carrying a BRCA1 mutation increases cancer risk, not every individual with such a mutation will develop cancer, indicating the influence of other genetic and environmental factors.
What the gene does
The BRCA1 protein is a complex tumour suppressor, primarily recognised for its central role in DNA repair, particularly homologous recombination. This is a high-fidelity mechanism for repairing double-strand breaks in DNA. Within the cell nucleus, the BRCA1 protein collaborates with a network of other proteins to detect and mend these breaks. Chromosomal damage can arise from diverse sources, ranging from naturally occurring cellular metabolism to medical radiation and environmental agents, and also during genetic exchange between chromosomes preparing for division. By efficiently resolving such breaks, BRCA1 maintains genome stability, preventing the accumulation of mutations that could lead to cancer.
Beyond its direct involvement in DNA repair, the BRCA1 protein helps preserve genomic stability by regulating gene expression and influencing cell cycle checkpoints. It acts as a scaffold for large protein complexes involved in ubiquitination, a process that tags proteins for degradation or alters their function. This is essential for coordinating DNA repair pathways. The protein's interaction with transcription factors can modulate the expression of genes involved in cell growth, differentiation, and apoptosis (programmed cell death). This regulatory capacity helps prevent cells with damaged DNA from dividing, thereby inhibiting tumour formation.
Furthermore, research indicates that the BRCA1 protein participates in regulating chromatin structure, influencing how DNA is packaged within the cell nucleus. This function can impact gene accessibility and repair efficiency. The intricate interplay between BRCA1 and numerous other proteins highlights its central role in cellular surveillance and response mechanisms. This illustrates why pathogenic variants in this gene can have significant health implications by compromising these critical protective functions.
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Chromosome location
The BRCA1 gene is located on chromosome 17, specifically at position 17q21.31. This genomic location refers to the long (q) arm of chromosome 17, within region 2, band 1, and sub-band 31. The BRCA1 gene spans a considerable length of DNA, comprising 22 exons. Its position on chromosome 17 means it is part of a region frequently associated with genetic alterations in various human cancers. The precise mapping of BRCA1 to this locus was a significant step in understanding its role in inherited cancer predisposition.
Protein structure
The BRCA1 protein, consisting of 1863 amino acids, exhibits a modular structure with several functionally important domains and disordered regions. At the N-terminus, specifically spanning amino acids 24-65, is the RING-type (Zinc finger) domain. This domain is critical for protein-protein interactions, particularly for its E3 ubiquitin ligase activity, which is essential for DNA repair and cell cycle regulation.
Several disordered regions are interspersed throughout the protein, suggesting flexibility and dynamic interactions with other molecular partners. These include regions at amino acids 230-270, 306-338, 534-570, 654-709, 1181-1216, 1322-1387, 1440-1505, and 1565-1596. These intrinsically disordered regions are often involved in molecular recognition and signalling within complex cellular pathways. An interaction region with PALB2 is located at amino acids 1397-1424, highlighting its cooperative role in homologous recombination DNA repair.
The C-terminus of the BRCA1 protein contains two BRCT domains: BRCT 1 from amino acids 1642-1736 and BRCT 2 from amino acids 1756-1855. These tandem BRCT domains are phosphopeptide-binding modules, crucial for recognising phosphorylated proteins that serve as markers of DNA damage. This recognition allows BRCA1 to be recruited to sites of DNA damage and coordinate repair processes.
Key variants
Genetic variations within the BRCA1 gene can range from single nucleotide changes to larger deletions or duplications. Pathogenic variants, often referred to as mutations, can disrupt the gene's ability to produce a functional protein or can lead to a protein with impaired function. These alterations can prevent the BRCA1 protein from effectively carrying out its roles in DNA repair and tumour suppression. The specific type and location of a variant can influence its impact on protein function and, consequently, the associated cancer risk. Variants are classified based on their predicted clinical significance, ranging from benign to pathogenic, to help guide clinical management.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.4358_4484del | - | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.1002del | p.Ser335fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1008dup | p.Glu337fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.101_105del | p.Pro34fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.1012A>T | p.Lys338Ter | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1016_1017insC | p.Lys339fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.1016del | p.Lys339fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.1016dup | p.Val340fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.1017_1018insA | p.Val340fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
c.1017_1018insC | p.Val340fs | Pathogenic | ★★★☆ | Breast-ovarian cancer, familial, susceptibility to, 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the BRCA1 gene are primarily associated with Hereditary breast and ovarian cancer syndrome, which is inherited in an autosomal dominant pattern. Individuals with these variants have a substantially increased lifetime risk of developing breast cancer, ovarian cancer, and a moderately increased risk of prostate cancer and pancreatic cancer. The specific cancer risks and their presentation can differ among individuals, even within the same family, influenced by other genetic and environmental factors. This increased risk applies to both men and women, although the types of cancer typically vary. Awareness of these associations is crucial for risk assessment and personalised screening strategies.
Inheritance pattern
Conditions caused by pathogenic BRCA1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the BRCA1 gene is widely recognised for its clinical significance and is included in numerous NHS national genomic testing panels. This ensures comprehensive assessment for individuals with a family history or clinical presentation suggestive of hereditary cancer syndromes. BRCA1 is listed on the 'Additional findings health related', 'Additional findings health related - adult specific', and 'Additional findings health related - CNV analysis adult specific' panels, indicating its importance in identifying secondary findings that may impact health management. It is also a key gene on panels for various cancers, including 'Adult solid tumours cancer susceptibility', 'Breast cancer pertinent cancer susceptibility', 'Childhood solid tumours cancer susceptibility', 'Familial breast cancer', 'Inherited breast cancer and ovarian cancer (R208)', 'Inherited ovarian cancer (without breast cancer) (R207)', 'Inherited pancreatic cancer (R367)', and 'Inherited prostate cancer (R430)'. Furthermore, BRCA1 is relevant for 'NICE approved PARP inhibitor treatment (R444)', highlighting its role in guiding therapeutic decisions. Its inclusion across such a broad spectrum of panels underscores its critical impact on genomic medicine in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with a known BRCA1 pathogenic variant, lifestyle modifications may be considered as part of a comprehensive risk management strategy, although they are not a substitute for clinical surveillance or medical interventions. General healthy lifestyle recommendations, such as maintaining a healthy body weight and limiting alcohol intake, are often discussed in the context of overall cancer risk reduction for the general population. Some research suggests that a diet rich in fruits, vegetables, and whole grains, and low in processed foods and red meat, may be associated with a reduced risk of certain cancers, though specific evidence for BRCA1 carriers is still evolving. Regular physical activity has also been linked to a lower risk of several cancers in the general population. However, it is important to understand that lifestyle factors alone cannot eliminate the significantly increased cancer risk associated with a BRCA1 mutation. Any lifestyle changes should be discussed with a healthcare professional as part of an individualised health plan.
Supplement considerations
Currently, there is no conclusive scientific evidence that specific dietary supplements can prevent cancer in individuals with BRCA1 pathogenic variants. While some supplements are marketed for their general health benefits or potential anti-cancer properties, these claims are generally not supported by robust clinical trials specifically in the context of BRCA1-related cancer prevention. For instance, some studies have explored the role of vitamin D or antioxidants in cancer risk, but the findings are often inconsistent or have not demonstrated a significant benefit for BRCA1 carriers. Individuals with BRCA1 mutations should always consult with a healthcare professional before taking any new supplements, as some may interact with medications or have unforeseen effects. The primary cancer prevention and screening strategies for BRCA1 carriers are well-established medical protocols, not supplement use.
Frequently asked questions
What is the main function of the BRCA1 gene?
The BRCA1 gene provides instructions for making a protein that acts as a tumour suppressor. Its primary function is to repair damaged DNA, which helps maintain the stability of a cell's genetic information and prevents uncontrolled cell growth.
What conditions are associated with BRCA1 mutations?
Pathogenic mutations in the BRCA1 gene are strongly associated with Hereditary breast and ovarian cancer syndrome, which significantly increases the risk of breast, ovarian, and to a lesser extent, prostate and pancreatic cancers.
Are BRCA1 mutations only inherited by women?
No, BRCA1 mutations can be inherited by both men and women. While they are more commonly associated with breast and ovarian cancer in women, men with BRCA1 mutations also face an increased risk of certain cancers, such as prostate cancer.
Can lifestyle changes prevent cancer with a BRCA1 mutation?
While a healthy lifestyle may contribute to overall well-being, lifestyle changes alone cannot eliminate the significantly increased cancer risk associated with a BRCA1 mutation. They should complement, not replace, medical surveillance and interventions.
Is genetic testing for BRCA1 available in the UK?
Yes, BRCA1 genetic testing is available in the UK, particularly for individuals with a family history or clinical presentation suggestive of hereditary cancer syndromes. It is included in multiple NHS national genomic testing panels.
What is a 'tumour suppressor' gene?
A tumour suppressor gene, like BRCA1, produces proteins that help control cell growth and division. These proteins can initiate programmed cell death (apoptosis) if DNA is damaged beyond repair, thus preventing the formation and growth of tumours.
References
- Oh M, McBride A, Yun S. BRCA1 and BRCA2 Gene Mutations and Colorectal Cancer Risk: Systematic Review and Meta-analysis. Journal of the National Cancer Institute. 2018. PMID: 30380096
- Toss A, Tomasello C, Razzaboni E. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. BioMed research international. 2015. PMID: 26075229
- Foulkes WD. BRCA1 and BRCA2 - update and implications on the genetics of breast cancer: a clinical perspective. Clinical genetics. 2014. PMID: 24116874
- Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. Journal of the National Cancer Institute. 2014. PMID: 24824314
- Foulkes WD, Shuen AY. In brief: BRCA1 and BRCA2. The Journal of pathology. 2013. PMID: 23620175
- Kobayashi H, Ohno S, Sasaki Y. Hereditary breast and ovarian cancer susceptibility genes (review). Oncology reports. 2013. PMID: 23779253
- Pennington KP, Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecologic oncology. 2012. PMID: 22264603
- Shulman LP. Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome. Obstetrics and gynecology clinics of North America. 2010. PMID: 20494261
- Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007. PMID: 17416853
- Walsh T, Casadei S, Coats KH. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006. PMID: 16551709
- Antoniou A, Pharoah PD, Narod S. 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. American journal of human genetics. 2003. PMID: 12677558
- Adam MP, Bick S, Mirzaa GM. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1993. PMID: 20301425