Associated disorders

The BRIP1 gene is associated with an increased risk for autosomal dominant breast and ovarian cancer in individuals who carry a single pathogenic BRIP1 variant. Additionally, the BRIP1 gene is associated with autosomal recessive Fanconi anemia (MedGen UID: 323015).

The BRIP1 gene encodes a helicase that interacts with the BRCT repeats of BRCA1. The bound complex is important in the normal double-strand break-repair function of BRCA1.

BRIP1 Heterozygote
MedGen UID: 87542

Clinical condition
Women who are carriers of a single pathogenic BRIP1 variant have an increased risk of breast and ovarian cancer. The exact risk figures for breast cancer have yet to be determined (PMID: 17033622 21964575 ); however, studies suggest the risk of ovarian cancer is approximately 8% (PMID: 17033622 21964575 26720728 26315354 ). There may also be an increased risk for other cancer types such as pancreatic, though the current evidence is limited (PMID: 21964575 ). An individual with a BRIP1 pathogenic variant will not necessarily develop cancer in their lifetime, but the risk for cancer is increased over the general population risk.

BRIP1 also has preliminary evidence of an association with hematologic malignancies, and is therefore available as a “preliminary-evidence” gene on Invitae’s Myelodysplastic Syndrome/Leukemia Panel. Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these limited evidence genes.

Gene information
The BRIP1 gene is required for the maintenance of chromosomal stability. It acts late in the Fanconi anemia pathway and is involved in the repair of DNA double-strand breaks by homologously recombining in a manner that depends on its association with BRCA1 ( UniProtKB – Q9BX63 ). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

Hereditary predisposition to cancer due to a single pathogenic variant in the BRIP1 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once such a variant is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). An individual with a variant in BRIP1 has a 50% risk of passing that variant on to offspring.

Additionally, individuals with a pathogenic variant in BRIP1 are carriers of Fanconi anemia type J. Fanconi anemia is an autosomal recessive disorder that is characterized by bone marrow failure and variable presentation of anomalies, including short stature, abnormal skin pigmentation, abnormal thumbs, malformations of the skeletal and central nervous systems, and developmental delay (PMID: 8986277 20417588 ). Risks for leukemia and early onset solid tumors are significantly elevated (PMID: 12393424 12393516 20507306 ). For there to be a risk of Fanconi anemia in offspring, both parents would each have to have a single pathogenic variant in BRIP1; in such a case, the risk of having an affected child is 25%.

The National Comprehensive Cancer Network (NCCN) recommends consideration of prophylactic salpingo-oophorectomy (surgical removal of the ovaries and fallopian tubes) for women with a pathogenic variant in BRIP1 after childbearing is complete ( National Comprehensive Cancer Network. Breast and Ovarian Management Based on Genetic Test Results. Version 1.2016 ). Women electing to defer prophylactic oophorectomy can consider screening for serum CA-125 and transvaginal ultrasound; however, data do not support such screening and it should not be a substitute for preventive surgery. The current NCCN guidelines do not recommend additional breast cancer screening for individuals with a single pathogenic BRIP1 variant beyond what is recommended for the general population. However, they caution that cancer screening should ultimately be guided by personal and family history ( National Comprehensive Cancer Network. Breast and Ovarian Management Based on Genetic Test Results. Version 1.2016 ).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though data regarding BRIP1 is limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding BRIP1 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: July 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
BRIP1 NM_032043.2