BRCA1 and BRCA2

BRCA1 and BRCA2 are tumour suppressor genes with a central role in the homologous recombination repair (HRR) pathway. HRR is the major pathway for the repair of double-stranded DNA breaks. This is clinically important as failure of this pathway means that precision treatment options may be available for patients affected with BRCA-deficient cancers (e.g. PARP inhibitors).

BRCA1

• Located at chromosome 17q21.31.
• Contains 22 exons, spanning approximately 110kb DNA.

BRCA2

• Located at chromosome 13q13.1.
• Contains 27 exons, spanning approximately 84kb DNA.

BRCA1 and BRCA2 both contain a number of functional domains in which missense variants are more likely to cause disease (for example, the DNA binding/RING binding domains).

• BRCA1 and BRCA2 are large genes in which multiple different types of pathogenic variants have been identified.
• The majority of these variants are individually rare and several have only been reported in single families (so called ‘private’ variants).
• Some founder mutations are present at increased frequency in certain ethnic groups:
  • Approximately 1 in 40 individuals of Ashkenazi Jewish ancestry carry a variant in BRCA1 or BRCA2, of which three founder variants account for greater than 90% of BRCA1/BRCA2 variants in this population:
    • BRCA1: c.68_69del (p.Glu23fs) (also known as BRCA1_185delAG)
    • BRCA1: c.5266dup (p.Gln1756fs) (also known as BRCA1_5382insC)
    • BRCA2: c.5946del (p.Ser1982fs) (also known as BRCA2_6174delT)
  • A single variant in BRCA2 (BRCA2: c.771_775del (p.Asn257fs); also known as BRCA2 999del5) is believed to account for approximately 7–8% of breast cancer in women and 40% of breast cancer in men of Icelandic ancestry.
  • There are a number of founder variants in BRCA1 in individuals of Polish descent, of which the three most common are:
    • BRCA1: c.5266dup (p.Gln1756fs) (also known as BRCA1_5382insC)
    • BRCA1: c.181T>G (p.Cys61Gly) (also known as BRCA1_300T>G)
    • BRCA1: c.4035del (p.Glu1346fs) (also known as BRCA1_4153delA)

The mutational spectra of BRCA1 and BRCA2 include:

• • Protein-truncating variants (i.e. nonsense mutations, frameshift mutations and essential splice site mutations).
  • Missense mutations: while the majority of missense variation in the BRCA1/2 genes is benign, pathogenic missense variants do occur, particularly in functional domains (see above). It is therefore important to consider the location of BRCA1 and BRCA2 missense variants during variant interpretation.
  • Exon deletions/duplications: up to 20% of pathogenic variants in BRCA1, and a smaller proportion of variants in BRCA2, may be large genomic rearrangements, depending on the patient population in question. This is an important consideration in individuals who had uninformative BRCA1/BRCA2 testing in the 1990s or early 2000s when testing was limited and dosage analysis to facilitate detection of such variants (for example, MLPA) was not routinely available. Repeat testing using updated technology may be warranted in such individuals.

Hereditary breast and ovarian cancer (HBOC)

Constitutional (germline) pathogenic variants in BRCA1 and BRCA2 are associated with a high risk of breast, ovarian and other cancers.

Estimated lifetime cancer risks for carriers of constitutional pathogenic variants in BRCA1/BRCA2 include:¹

*Note: Risks in transwomen are uncertain, but are likely to be lower than those in women but higher than those in men.

** including tubal and primary peritoneal cancers.

• Approximately 80% of breast cancers occurring in carriers of constitutional (germline) pathogenic variants in BRCA1 are triple-negative (specifically the basal subtype), but breast cancers in carriers of BRCA2 variants are more heterogeneous.
• Ovarian cancer occurring in carriers of pathogenic BRCA1/BRCA2 variants is typically of the high-grade serous subtype. Most cases of ovarian cancer occur after the age of 40 in carriers of pathogenic BRCA1 variants, and after the age of 50 in carriers of pathogenic BRCA2 variants.
• Prostate cancer occurring in male carriers of BRCA1/BRCA2 variants is typically more aggressive, occurs at younger than expected ages, and has higher metastatic potential than prostate cancer occurring in the general population.
• Tumours occurring in carriers of pathogenic variants in BRCA1/BRCA2 may demonstrate homologous recombination repair deficiency (HRD) – a biomarker of response to PARP inhibition, and may demonstrate characteristic mutation signatures, indicating ‘BRCAness’. Sporadic cancers occurring by chance (for example, lung or skin cancers) in carriers of such variants may not demonstrate these features.
• Other cancers, including stomach cancer and melanoma, have been reported with increased frequency in carriers of pathogenic variants in BRCA1/BRCA2. Confirmation of such associations and risks of such cancers have yet to be determined.

Recessive disorders associated with pathogenic variants in BRCA1/BRCA2

• Individuals that carry pathogenic variants in both copies of their BRCA2 gene (biallelic variants) are affected by a condition known as Fanconi anaemia, a chromosomal fragility syndrome characterised by congenital abnormalities of the skeleton, eye or genitourinary system, short stature, progressive bone marrow failure and predisposition to haematological and solid tumours.
• Biallelic pathogenic variants in BRCA1 are typically embryonically lethal, but survivors have been reported, the majority of whom demonstrate a severe phenotype overlapping with that of Fanconi anaemia and other DNA repair defects, as part of a condition now known as BRCA1 deficiency.
  • Affected individuals demonstrate pre- and post-natal growth failure, microcephaly, dysmorphic features and increased predisposition to cancer.
• Rarely, individuals may inherit a pathogenic variant in one copy (monoallelic) of BRCA1 as well as a monoallelic pathogenic variant in BRCA2.
  • This is more common in individuals from populations where founder variants are common, such as people of Ashkenazi Jewish heritage. Such individuals are known as ‘double heterozygotes’ or ‘transheterozygotes’.
  • The phenotype in such individuals is largely indistinguishable from the phenotype in carriers of only one variant in either BRCA1 or BRCA2.

• Constitutional (germline) genetic testing of BRCA1 and BRCA2 is available through the National Genomic Test Directory for individuals affected by breast, ovarian or pancreatic cancer who meet the eligibility criteria.
• Tumour-based (somatic) testing of BRCA1 and BRCA2 is available for all patients with prostate cancer or high-grade serous ovarian cancer, and for patients with pancreatic cancer where treatment with PARP inhibitors may be considered.
• BRCA1 and BRCA2 are also included in the gene panel test for individuals with confirmed Fanconi anaemia.

• Cancer risk associated with constitutional (germline) BRCA1/BRCA2 variants is inherited in an autosomal dominant pattern.
• First-degree relatives of a carrier of a pathogenic variant in BRCA1 or BRCA2 are at 50% risk of carrying the familial variant.
• Carriers should be referred to clinical genetics for genetic counselling and cascade screening.

In addition to condition-specific information below, referral of patients found to carry variants in BRCA1 or BRCA2 to clinical genetics should be arranged to discuss onward management, family planning implications and cascade testing of at-risk relatives.

Breast cancer

Female carriers

Female carriers of pathogenic BRCA1/BRCA2 variants have a number of options for management of their increased breast cancer risk, including:

Very high risk (VHR) breast cancer screening

• This is typically indicated from the age of 30, but may be considered from as young as 25 in patients with an estimated 10-year risk (calculated by CanRisk) of at least 8%.
• Screening consists of a combination of MRI and/or mammogram depending on age and breast density:
  • Age 25/30-40: annual MRI
  • Age 40-50: annual MRI and annual mammogram
  • Age 50+ mammogram only

Risk-reducing breast surgery

• Many women may choose to undergo risk-reducing bilateral mastectomy, which is usually followed by immediate reconstruction where possible.
• The residual risk of breast cancer after risk-reducing prophylactic mastectomy is less than 5%.
• The survival advantage of surgery compared to surveillance is uncertain, but appears to be small, and diminishes rapidly with increasing age.
• Contralateral prophylactic mastectomy in a patient who has already been affected by breast cancer may be considered, and, if feasible, may be undertaken at the same time as therapeutic mastectomy.
• Contralateral prophylactic surgery will minimise the risk of a second primary breast cancer, but the risk of metastatic recurrence from the first breast cancer should be carefully considered when counselling the patient about the potential advantages of this surgery.

Chemoprophylaxis

• Guidance from NICE (National Institute of Clinical Excellence) published in March 2017 recommends that chemoprevention with tamoxifen, raloxifene or anastrozole should be considered in women at increased risk of breast cancer based on their family history, after giving due consideration to potential contraindications and risks of adverse events.
• Chemoprophylaxis with such agents may be considered in unaffected carriers of pathogenic variants in BRCA2, but the use of such agents in carriers of pathogenic variants in BRCA1 is less clear given that the majority of breast cancers in such individuals are not hormone receptor-positive.

Male carriers

Breast cancer screening is not recommended in male carriers of pathogenic BRCA1/BRCA2 variants, but breast symptom awareness is encouraged.

Tubo-ovarian cancer

• Ovarian cancer screening has not, as yet, been found to impact mortality from the disease.
• At present, the only proven method of minimising the risk of tubo-ovarian cancer in women at higher risk is to undergo risk-reducing ovarian surgery. Following this surgery, a residual risk of primary peritoneal cancer persists, which is estimated to be <4%.
• Considering that risks before age 35 are low, the risks associated with premature menopause at that age may outweigh potential benefit, such that risk-reducing ovarian surgery is not typically undertaken before that age. Considerations should also be given to fertility and family planning.
• In carriers of pathogenic variants in BRCA1/BRCA2 that undergo risk-reducing bilateral salpingo-oophorectomy, hormone replacement therapy is recommended to minimise risks associated with premature menopause, unless the patient has a preceding personal history of ER/PR-positive breast cancer.

Pancreatic cancer

• As screening has not yet been proven to impact mortality from pancreatic cancer, the consensus from the UK Cancer Genetics Group is that screening for this type of cancer should not be offered outside of research studies.
• Patients should be counselled regarding modifiable risk factors (including smoking) and symptom awareness.

Prostate cancer

• Current evidence suggests that PSA-based screening annually, starting from the age of 40, with MRI and biopsy as required, may facilitate early detection of prostate cancer in carriers of constitutional (germline) pathogenic BRCA2 variants.
• Longer follow up is required to determine if this approach is useful in carriers of pathogenic BRCA1 variants.

• The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genetic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one potential parent is a carrier of a pathogenic variant in BRCA1/BRCA2. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.
• Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

For clinicians

• Gene Reviews: BRCA1– and BRCA2-Associated Hereditary Breast and Ovarian Cancer
• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: Familial breast cancer guidelines: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• OMIM (Online Mendelian Inheritance in Man): Online catalogue of human genes and genetic disorders
• Public Health England: Protocols for surveillance of women at very high risk of breast cancer
• UK Cancer Genetics Group: Very High Risk Breast Screening information

References:

• ¹ Kuchenbaecker KB, Hopper JL, Barnes DR and others. ‘Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers‘. JAMA 2017: volume 317, issue 23, pages 2402-2416. doi: 10.1001/jama.2017.7112

For patients

• The Royal Marsden NHS Foundation Trust: A Beginner’s Guide to BRCA1 and BRCA2
• The Royal Marsden NHS Foundation Trust: Cancer genetics information videos