BRCA1 and BRCA2

BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 1 (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, because failure of the pathway means that precision treatment options such as PARP inhibitors may be available for patients affected with BRCA-deficient cancers.

• BRCA1 is located at chromosome 17q21.31 and contains 22 exons, spanning approximately 110kb DNA.
• BRCA2 is located at chromosome 13q13.1 and 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).

Approximately 1 in 381 people in the general population have a constitutional (germline) pathogenic variant in BRCA1, and 1 in 277 in BRCA2. Founder events mean that the frequency of variants in these genes is higher in certain ethnic groups; for example, approximately 1 in 40 individuals of Ashkenazi Jewish ancestry have a variant in BRCA1 or BRCA2.

• BRCA1 and BRCA2 are large genes in which multiple different types of pathogenic variant have been identified.
• The majority of these variants are individually rare, and several have only been reported in single families (so-called ‘private’ variants).
• Certain founder variants are present at increased frequency in certain ethnic groups, as outlined below.
  • Three founder variants account for greater than 90% of BRCA1 and BRCA2 variants in individuals of Ashkenazi Jewish heritage:
    • BRCA1: c.68_69del (p.Glu23fs) (also known as BRCA1_185delAG);
    • BRCA1: c.5266dup (p.Gln1756fs) (also known as BRCA1_5382insC); and
    • 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 of Icelandic ancestry 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); and
    • BRCA1: c.4035del (p.Glu1346fs) (also known as BRCA1_4153delA).

The pathogenic variant spectra of BRCA1 and BRCA2 include the below.

• Protein-truncating variants (that is, nonsense variants, frameshift variants and essential splice site variants).
• Missense variants: while the majority of missense variation in the BRCA1 and BRCA2 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 and 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 or BRCA2 testing in the 1990s or early 2000s, when testing was limited and dosage analysis to facilitate detection of such variants (for example, multiplex ligation-dependent probe amplification (MLPA)) was not routinely available. Repeat testing using updated technology may be warranted in such individuals.

Hereditary breast and ovarian cancer

Constitutional (germline) pathogenic variants in BRCA1 and BRCA2 are associated with a high risk of breast, ovarian, prostate, pancreatic and other cancers. For estimated lifetime cancer risks, see table 1.

Table 1: Estimated lifetime cancer risks for those with constitutional (germline) pathogenic variants in BRCA1 or BRCA2

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

Recessive conditions associated with pathogenic variants in BRCA1 and BRCA2

• Individuals with 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 anomalies 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 in which 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 those with only one variant in either BRCA1 or BRCA2.

• Constitutional (germline) testing of BRCA1 and BRCA2 is available as part of larger multi-gene panels for individuals affected by breast (R208), ovarian (R207), prostate (R430) or pancreatic cancer (R367) who meet eligibility criteria as laid out in the National Genomic Test Directory on the basis of their personal or family history of cancer.
• Patients with breast or prostate cancer not fulfilling eligibility criteria for constitutional (germline) testing of BRCA1 or BRCA2 via R208 or R430 indications may be offered testing under R444 if a positive result would render them eligible for NICE-approved PARP inhibitor treatment. For patients with prostate cancer, somatic (tumour) testing should be attempted first.
• Somatic (tumour) testing of BRCA1 and BRCA2 is available for patients with prostate cancer and high-grade serous ovarian cancer to determine eligibility for treatment with PARP inhibitors. PARP inhibitors are not currently available in the NHS for pancreatic cancer, but somatic (tumour) testing of pancreatic tissue for BRCA1 or BRCA2 may be performed if it will influence clinical trial access. If a variant is identified and constitutional (germline) BRCA1 or BRCA2 testing has not previously been undertaken, site-specific testing on constitutional DNA (usually from blood) is required to determine whether the variant is of somatic or constitutional origin.
• BRCA1 and BRCA2 testing is also available for individuals with a suspected diagnosis of Fanconi anaemia under indications R359 (childhood solid tumours), R229 (confirmed Fanconi anaemia or Bloom syndrome), R258 (cytopenia) and R236 (pigmentary skin disorders).

• Cancer risk associated with constitutional (germline) BRCA1 or BRCA2 variants is inherited in an autosomal dominant pattern.
• First-degree relatives of an individual with a pathogenic variant in BRCA1 or BRCA2 are at 50% risk of having the familial variant.
• Those with the variant should be referred to clinical genetics services for genomic counselling and cascade screening.
• Because of the potential for recessive phenotypes in children of two individuals with variants in BRCA1 or BRCA2, testing of partners or spouses for variants in the same gene should be considered where relationships are consanguineous, or if the partner or spouse is from an ethnic group in which frequency of variants in BRCA1 and/or BRCA2 is high.

In addition to the condition-specific information below, please note that patients found to have variants in BRCA1 or BRCA2 should be referred to clinical genetics services to discuss onward management, family planning implications and cascade testing of at-risk relatives.

Breast cancer

Females with pathogenic BRCA1 or BRCA2 variants

Females with pathogenic BRCA1 or BRCA2 variants have a number of options for management of their increased breast cancer risk, including the below.

Very high-risk 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 25–40: annual MRI;
  • age 40–50: annual MRI and annual mammogram; and
  • age 50 and over: 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, updated in 2023, 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 people with pathogenic variants in BRCA2, but the use of such agents in people with pathogenic variants in BRCA1 is less clear, given that the majority of breast cancers in such individuals are not hormone receptor-positive.

Males with pathogenic variants in BRCA1 or BRCA2

Breast cancer screening is not recommended in males with pathogenic BRCA1 or BRCA2 variants, but breast symptom awareness is encouraged.

Tubo-ovarian cancer

• Screening has not, as yet, been found to impact mortality from tubo-ovarian cancer.
• At present, the only proven method of minimising the risk of tubo-ovarian cancer in women at higher risk is to undergo risk-reducing bilateral salpingo-oophorectomy. Following this surgery, a residual risk of primary peritoneal cancer persists, which is estimated to be less than 4%. Residual risk of primary peritoneal cancer is highest in women who have evidence of serous tubal intraepithelial carcinoma in the fallopian tubes.
• Considering that risks of tubo-ovarian cancer before age 35 are low, and the risks associated with premature menopause at that age may outweigh potential benefits, risk-reducing ovarian surgery is not typically undertaken before that age. Considerations should also be given to fertility and family planning.
• In those with pathogenic variants in BRCA1 or BRCA2 who 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 oestrogen receptor- or progesterone receptor-positive breast cancer.
• Most BRCA-associated serous gynaecological cancers are believed to start in the fallopian tube. Research is ongoing to determine efficacy and acceptability of a two-staged approach starting with early bilateral salpingectomy and delayed oophorectomy.

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 prostate-specific antigen-based screening annually, starting from the age of 40, with MRI and biopsy as required, may facilitate early detection of prostate cancer in those with constitutional (germline) pathogenic BRCA2 variants.
• Longer follow-up is required to determine whether this approach is useful in those with pathogenic BRCA1 variants.

• The Human Fertilisation and Embryology Authority has approved the use of preimplantation genomic testing for monogenic disorders (PGT-M) (previously known as preimplantation genetic diagnosis) for couples in whom one or both intended parent(s) has a pathogenic variant in BRCA1 or 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 has the variant) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

• BRCA1and BRCA2 are tumour suppressor genes. Variants in these genes are associated with a predisposition to multiple different cancers, not only breast and ovarian cancer.
• Some ethnic groups have particular variants in these genes at higher frequencies than the general population, but many variants are individually rare and may only be found in a single family.
• When disease associated variants are identified in a patient, they may choose to take risk-reducing measures including screening, surgery or chemoprophylaxis.

For clinicians

• GeneReviews: BRCA1- and BRCA2-associated hereditary breast and ovarian cancer
• Gov.uk Guidance: Protocols for surveillance of women at higher risk of developing breast cancer
• NHS England: National Genomic Test Directory
• NICE: Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• Online Mendelian Inheritance in Man (OMIM)
• UK Cancer Genetics Group: Leaflets and guidelines
• UK Cancer Genetics Group: Very high risk breast cancer screening

References:

• Kuchenbaecker KB, Hopper JL, Barnes DR and others. ‘Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers‘. The Journal of the American Medical Association 2017: volume 317, issue 23, pages 2,402–2,416. DOI: 10.1001/jama.2017.7112
• Li S, Silvestri V, Leslie G and others. ‘Cancer risks associated with BRCA1 and BRCA2 pathogenic variants‘. Journal of Clinical Oncology 2022: volume 40, issue 14, pages 1,529–1,541. DOI: 10.1200/JCO.21.02112

For patients

• NICE: Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• The Royal Marsden NHS Foundation Trust: A beginner’s guide to BRCA1 and BRCA2
• The Royal Marsden NHS Foundation Trust: Cancer genetics
• UK Cancer Genetics Group: Leaflets and guidelines