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BRCA2

Alias

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

Associated disorders

The BRCA2 gene is associated with autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome (MedGen UID: 151793) and autosomal recessive Fanconi anemia, type D1 (FA-D1) (MedGen UID: 325420).

The BRCA2 gene encodes a nuclear phosphoprotein that plays a role in the homologous recombination pathway for double-stranded DNA repair. As a tumor suppressor gene, loss of BRCA2 protein function leads to genomic instability and malignant transformation.

BRCA1 and BRCA2
(please note that two separate clinic notes are included below)

BRCA1

Clinical condition
The average woman’s lifetime risk of developing breast cancer is 12%; her risk for developing ovarian cancer is 1.3% (SEER database 2014. https://seer.cancer.gov/data. Accessed September 2017). Most cases of these cancers are sporadic and are not due to hereditary factors, but approximately 5-10% of breast and ovarian cancer cases are hereditary and due to an identifiable pathogenic variant in a disease-causing gene. Hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants in the BRCA1 and BRCA2 genes accounts for the majority of hereditary breast and ovarian cancer cases in individuals with a strong family history or an early-onset diagnosis.

HBOC syndrome is characterized by an increased lifetime risk for generally adult-onset cancers including breast, contralateral breast, male breast, ovarian, prostate, and pancreatic (PMID: 12237281).

The cancers associated with BRCA1 are:

BRCA1 also has preliminary evidence for an association with melanoma (PMID: 22187320) and hematologic malignancy (PMID:17683622). Therefore, this gene is available as a “preliminary-evidence” gene on the Invitae’s Melanoma and 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 preliminary-evidence genes.

Gene information
BRCA1 is a tumor suppressor gene whose encoded protein is also involved in maintaining genomic stability. BRCA1 combines with other tumor suppressors in the DNA damage repair pathway. The BRCA1 protein is involved in transcription, DNA repair of double-stranded breaks, and recombination (NCBI Gene. Gene ID: 672. https://www.ncbi.nlm.nih.gov/gene/672. Accessed September 2017). If there is a pathogenic variant in this gene that prevents it from functioning normally, there may be an increased risk to develop certain cancers.

Inheritance
Hereditary predisposition to cancer due to pathogenic variants in the BRCA1 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to his/her offspring. Most cases are inherited from a parent, but some cases may occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). Identification of a pathogenic variant allows for the recognition of at-risk relatives who can pursue testing for the familial variant.

Management
Management Guidelines for individuals with pathogenic BRCA1 variants have been developed by the National Comprehensive Cancer Network® (NCCN®):

NCCN breast cancer surveillance:

Females:

  • Breast awareness starting at age 18
  • Clinical breast exams every 6-12 months beginning at 25 years of age or at the age of the earliest diagnosed breast cancer in the family, if below age 25
  • Annual breast MRIs with contrast beginning between the ages of 25 and 29 (or annual mammograms if MRI is unavailable), although the age to initiate screening may be individualized based on family history
  • Annual breast MRI with contrast and annual mammography between the ages of 30 and 75
  • After age 75, management should be considered on an individual basis
  • For women treated for breast cancer, screening of remaining breast tissue with annual mammography and breast MRI should continue
  • Consider risk-reducing mastectomy and counsel regarding degree of protection, degree of cancer risk, and reconstruction options
    • Address the psychosocial, social, and quality-of-life aspects of undergoing risk-reducing mastectomy
  • Recommend risk-reducing salpingo-oophorectomy, typically between age 35 and 40 years and upon the completion of childbearing
  • Transvaginal ultrasound and serum CA-125, considered at the clinician’s discretion beginning between age 30 and 35 years
  • Consider risk-reducing agents as options for breast and ovarian cancer

Males:

  • Breast self-exam training and education starting at age 35 years
  • Clinical breast exam every 12 months, beginning at age 35 years
  • Consider prostate-cancer screening beginning at age 45 years

Pancreatic cancer:
NCCN cites insufficient evidence to warrant screening for pancreatic cancer (*NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017. Accessed September 11, 2017). In contrast, the American College of Gastroenterology Clinical Guidelines recommend pancreatic cancer screening in BRCA1 carriers be limited to those with a first- or second-degree relative affected with pancreatic cancer. Ideally, screening should be performed in experienced centers utilizing a multidisciplinary approach under research conditions. Recommended screening includes annual endoscopic ultrasound and/or MRI of the pancreas starting at age 50 or 10 years younger than the earliest age of pancreatic cancer diagnosis in the family (PMID: 25645574).

Additional risk reduction and management considerations:

  • Chemoprevention can reduce the risk of breast cancer in the contralateral breast in women with BRCA1 and BRCA2 mutations who have been diagnosed with breast cancer (PMID: 9747868, 11130383).
  • Oral contraceptive use has been shown to reduce the risk of ovarian cancer by approximately 60% in BRCA mutation carriers if taken for at least 5 years (PMID: 9700175).
  • Recent studies have some preliminary data that suggest PARP inhibitors may be a beneficial chemotherapeutic agent for a subset of patients with BRCA-associated breast and ovarian cancers. Clinical trials are currently in process to determine if and how these agents can be useful in the treatment of BRCA cancer patients (PMID: 20643861).

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, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if a BRCA1 pathogenic variant is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant BRCA1 data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

BRCA2

Clinical condition
The average woman’s lifetime risk of developing breast cancer is 12%; her risk for developing ovarian cancer is 1.3% (SEER database 2014. https://seer.cancer.gov/data. Accessed September 2017). Most cases of these cancers are sporadic and are not due to hereditary factors, but approximately 5%-10% of breast and ovarian cancer cases are hereditary and due to an identifiable pathogenic variant in a disease-causing gene. Hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants in the BRCA1 and BRCA2 genes accounts for the majority of hereditary breast and ovarian cancer cases in individuals with a strong family history or an early-onset diagnosis.

HBOC syndrome is characterized by an increased lifetime risk for generally adult-onset cancers including, breast, contralateral breast, male breast, ovarian, prostate, and pancreatic (PMID: 12237281).

The cancers associated with BRCA2 are:

BRCA2 also has preliminary evidence for an association with hematologic malignancy (PMID: “(external)17683622”:http://ncbi.nlm.nih.gov/pubmed/17683622); therefore, this gene is available as a “preliminary-evidence” gene on the Invitae Myelodysplastic Syndrome/Leukemia Panel11. 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 preliminary-evidence genes.

Gene information
The BRCA2 gene encodes a nuclear phosphoprotein that plays a role in the homologous recombination pathway for double-stranded DNA repair. As a tumor suppressor gene, loss of BRCA2 protein function leads to genomic instability and malignant transformation. If there is a pathogenic variant in this gene that prevents it from functioning normally, there may be an increased risk to develop certain cancers (NCBI Gene. Gene ID: 675. https://www.ncbi.nlm.nih.gov/gene/675. Accessed September 2017).

Inheritance
Hereditary predisposition to cancer due to pathogenic variants in the BRCA2 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to his/her offspring. Most cases are inherited from a parent, but some cases may occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). Identification of a pathogenic variant allows for the recognition of at-risk relatives who can pursue testing for the familial variant.

Individuals with a single pathogenic BRCA2 variant are also carriers of autosomal recessive Fanconi anemia. Fanconi anemia is characterized by bone marrow failure with variable additional anomalies, which often include short stature, abnormal skin pigmentation, abnormal thumbs, malformations of the skeletal and central nervous systems, and developmental delay (PMID: 8986277, 20417588). Risk of leukemia and early-onset solid tumors is significantly elevated with this disorder (PMID: 12393424, 12393516, 20507306). For there to be a risk of Fanconi anemia in offspring, both the patient and their partner would each have to carry a pathogenic variant in BRCA2; in this case, the risk to have an affected child is 25%.

Management
Management guidelines for individuals with pathogenic BRCA2 variants have been developed by the National Comprehensive Cancer Network® (NCCN®):

NCCN breast cancer surveillance:

Females:

  • Breast awareness starting at age 18
  • Clinical breast exams every 6-12 months beginning at 25 years of age or at the age of the earliest diagnosed breast cancer in the family.
  • Annual breast MRIs with contrast beginning between the ages of 25 and 29 (or annual mammograms if MRI is unavailable), although the age to initiate screening may be individualized based on family history
  • Annual breast MRI with contrast and annual mammography between the ages of 30 and 75
  • After age 75, management should be considered on an individual basis
  • For women treated for breast cancer, screening of remaining breast tissue with annual mammography and breast MRI should continue
  • Consider risk-reducing mastectomy, and counsel regarding degree of protection, degree of cancer risk, and reconstruction options
    • Address the psychosocial, social, and quality-of-life aspects of undergoing risk-reducing mastectomy
  • Recommend risk-reducing salpingo-oophorectomy, typically between age 35 and 40 years and upon the completion of childbearing, but it is reasonable to consider delaying until 40-45 years for BRCA2 carriers if patient has already maximized their breast cancer prevention (i.e., bilateral mastectomy).
  • Transvaginal ultrasound and serum CA-125, considered at the clinician’s discretion beginning between age 30 and 35 years
  • Consider risk-reducing agents as options for breast and ovarian cancer

Males:

  • Breast self-exam training and education starting at age 35 years
  • Clinical breast exam every 12 months, beginning at age 35 years
  • Consider prostate-cancer screening beginning at age 45 years

Pancreatic cancer:
NCCN cites insufficient evidence to warrant screening for pancreatic cancer (*NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017. Accessed September 11, 2017). In contrast, the American College of Gastroenterology Clinical Guidelines recommend pancreatic cancer screening in BRCA2 carriers be limited to those with a first- or second-degree relative affected with pancreatic cancer. Ideally, screening should be performed in experienced centers utilizing a multidisciplinary approach under research conditions. Recommended screening includes annual endoscopic ultrasound and/or MRI of the pancreas starting at age 50 or 10 years younger than the earliest age of pancreatic cancer diagnosis in the family (PMID: 25645574).

Additional risk reduction and management considerations:

  • Chemoprevention can reduce the risk of breast cancer in the contralateral breast in women with BRCA1 and BRCA2 mutations who have been diagnosed with breast cancer (PMID: 9747868, 11130383).
  • Oral contraceptive use has been shown to reduce the risk of ovarian cancer by approximately 60% in BRCA mutation carriers if taken for at least 5 years (PMID: 9700175).
  • Recent studies have some preliminary data that suggest PARP inhibitors may be a beneficial chemotherapeutic agent for a subset of patients with BRCA2-associated breast and ovarian cancers. Clinical trials are currently in process to determine if and how this agent can be useful in the treatment of BRCA2 cancer patients (PMID: 20643861).

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, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if a BRCA2 pathogenic variant is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant BRCA2 data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Additional references
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V.1.2017. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed September 7, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Review date: September 2017

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
BRCA2* NM_000059.3


*BRCA2: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.