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BRIP1
BRCA1 interacting DNA helicase 1
The BRIP1 gene provides instructions for making a protein critical for DNA repair, particularly in the pathways that maintain genomic stability and prevent abnormal cell growth. BRIP1, also known as BRCA1 interacting DNA helicase 1, produces a protein that interacts with the well-known BRCA1 protein to help repair damaged DNA.
BRIP1 is located on the long (q) arm of chromosome 17, at band 17q23.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The BRIP1 gene, which stands for BRCA1 interacting DNA helicase 1, encodes a protein that plays a crucial role in maintaining the integrity of our genetic material. This protein is involved in the repair of DNA damage, a process essential for preventing errors during cell division and protecting against uncontrolled cell growth.
Changes or variants in the BRIP1 gene can impair its normal function, which has been linked to an increased susceptibility to certain cancers, notably ovarian cancer.
What the gene does
The BRIP1 protein functions primarily as a DNA helicase, an enzyme that unwinds the double helix of DNA. This unwinding is a necessary step during DNA replication and repair processes. Specifically, BRIP1 works in concert with the BRCA1 protein to initiate a critical DNA repair pathway known as homologous recombination.
Within the cell, the BRIP1 protein helps to detect different types of DNA damage, including double-strand breaks. Its helicase activity is instrumental in preparing the damaged DNA for repair, ensuring genomic stability. When BRIP1 function is compromised by pathogenic variants, these repair mechanisms become less efficient, which can lead to an accumulation of DNA errors and an increased risk of cellular transformation into cancer cells.
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Chromosome location
The BRIP1 gene is located on chromosome 17 at position 17q23.2. This specific genomic address indicates its precise neighbourhood within the human genome.
Protein structure
The BRIP1 protein comprises 1249 amino acids and features several distinct functional regions. It contains a Helicase ATP-binding domain spanning amino acids 11-442, which is critical for its enzymatic activity. A Disordered region is found from amino acids 102-131. A Nuclear localisation signal, located at amino acids 158-175, directs the protein to the cell's nucleus, where DNA repair occurs. The DEAH box motif at amino acids 393-396 is characteristic of a family of helicases. Additionally, a specific Interaction with BRCA1 region (amino acids 888-1063) highlights its functional partnership. Further Disordered regions are present at amino acids 1018-1042 and 1108-1127.
Key variants
Variants in the BRIP1 gene can impact the protein's structure and function, potentially reducing its ability to correctly repair DNA. These changes can range from single nucleotide alterations to larger deletions or insertions, and their impact on protein function can vary significantly. Some variants are considered pathogenic or likely pathogenic because they are known to disrupt BRIP1's role in DNA repair, while others may be benign or of uncertain significance.
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.630_637delCCCTGGCC | - | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1004G>A | p.Trp335Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1005G>A | p.Trp335Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1015G>T | p.Glu339Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1018_1019insCT | p.Leu340fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial cancer of breast |
c.103G>T | p.Gly35Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group J |
c.1045G>C | p.Ala349Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group J |
c.1052_1055dup | p.Tyr353fs | Pathogenic | ★★☆☆ | Familial cancer of breast |
c.1058dup | p.Tyr353Ter | Pathogenic | ★★☆☆ | Fanconi anemia complementation group J |
c.1066C>T | p.Arg356Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
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 BRIP1 gene are associated with an increased genetic predisposition to certain cancers. Most notably, these variants have been linked to an elevated risk of inherited ovarian cancer. While BRIP1's role in other conditions is researched, its primary clinical association is with cancer susceptibility.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic BRIP1 variants typically follow ad/ar inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the BRIP1 gene is included in several NHS Genomic Medicine Service national testing panels. This indicates its recognised clinical relevance for conditions such as Adult solid tumours cancer susceptibility, Inherited ovarian cancer (without breast cancer), and Childhood solid tumours, among others. Its status as 'green' on these panels signifies that there is sufficient evidence for routine testing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the BRIP1 gene?
The BRIP1 gene produces a protein that acts as a DNA helicase, an enzyme crucial for unwinding DNA during the repair process. This protein works alongside BRCA1 to fix damaged DNA, helping to maintain genomic stability.
How can variants in BRIP1 affect health?
Pathogenic variants in the BRIP1 gene can impair the DNA repair machinery, leading to an accumulation of genetic errors. This increased genomic instability is associated with a higher risk of developing certain cancers, particularly ovarian cancer.
Is BRIP1 testing available in the UK?
Yes, BRIP1 is part of several NHS Genomic Medicine Service national testing panels in the UK, including those for inherited ovarian cancer and various solid tumour susceptibilities. This signifies its established clinical importance for genetic testing.