BRCA1 and BRCA2 gene changes: cancer risk, testing and options

Both genes are present in every cell and help to mend double-strand breaks in DNA. Cancer Research UK describes them as tumour suppressor genes: when they work, cells are stopped from growing and dividing out of control. When one copy carries a harmful change, the repair system is weaker and cancer is more likely to develop over a lifetime.

Doctors use several words for the same thing, including variant, fault, alteration and mutation. A harmful inherited change is called a pathogenic or likely pathogenic variant. Because it is present from conception it sits in nearly every cell of the body, which is why the NHS Genomics Education Programme refers to it as constitutional or germline, as opposed to the changes that arise in a single tumour.

The estimated frequency in the general population is about 1 in 381 for BRCA1 and 1 in 277 for BRCA2 according to the NHS Genomics Education Programme. Some variants recur in particular communities. Three founder variants account for more than 90% of BRCA1 and BRCA2 changes in people of Ashkenazi Jewish heritage, and other founder variants have been described in people of Icelandic and Polish descent.

A parent with a change in one copy of BRCA1 or BRCA2 passes on either the working copy or the changed copy at random, so each child has a 50% chance of inheriting the change. Both sexes can carry and pass it on. A man with a BRCA change may never develop cancer himself and still have a daughter who inherits the risk, which is one reason a family can look as though cancer skips a generation.

Cancer Research UK notes that other factors need to be in place for a cancer to develop, and that some inherited cancer genes are more likely to cause cancer than others. The extra ingredients are still being worked out, so two relatives with the same variant can have quite different histories.

A rarer situation arises if two carriers have a child. The NHS Genomics Education Programme explains that a child who inherits a damaged BRCA2 gene from both parents is affected by Fanconi anaemia, a different and serious condition. For this reason partners may be offered testing for the same gene where the relationship is consanguineous or where the partner comes from a community in which these variants are common.

The NHS Genomics Education Programme gives estimated lifetime risks for carriers alongside the risks for the general population. They are estimates, with wide ranges, and they describe groups rather than predicting what will happen to one person. Cancer Research UK quotes a similar picture: around 70 in 100 women with a change in either gene develop breast cancer by 80, and fewer than 10 in 100 men with a BRCA2 change do.

• Roughly 80% of breast cancers in BRCA1 carriers are triple-negative, whereas breast cancers in BRCA2 carriers are more varied.

• Ovarian cancer in carriers most often occurs after 40 for BRCA1 and after 50 for BRCA2.

• Prostate cancer in men with these variants tends to be more aggressive and to appear at younger ages than in other men.

The NHS says genetic testing is free if a hospital specialist refers you, and that it is generally offered when a genetic condition is suspected or you have a particular type of cancer. In practice a GP who hears about a strong family history, such as several close relatives on the same side with breast, ovarian, prostate or pancreatic cancer, or cancers at young ages, can refer to a clinical genetics service. There a genetic counsellor reviews the family tree and decides whether a test is appropriate.

People who already have breast, ovarian, prostate or pancreatic cancer can qualify through the criteria in the National Genomic Test Directory. For some, such as people with high-grade serous ovarian cancer or prostate cancer, testing may be done on the tumour as well, because the result can show whether PARP inhibitor treatment is an option.

Separately, the NHS says adults of 18 or over with at least one Jewish grandparent can have NHS genetic testing for BRCA faults through the NHS Jewish BRCA testing programme, without needing a strong family history.

Testing usually uses a blood or saliva sample. When a relative already has a known variant, testing is targeted at that single change, which is called predictive or cascade testing. Cancer Research UK points out that children under 18 cannot usually be tested, so that adults can make their own choice. Results can take weeks or months, and a result can be positive, negative, or an uncertain variant that cannot yet be interpreted.

Decisions are personal and are made with a genetics team. The NHS Genomics Education Programme sets out the options considered in the UK.

• Breast screening for very high risk: usually from age 30, sometimes from 25 if the estimated 10-year risk is at least 8%. It is annual MRI between 25 and 40, MRI plus mammogram between 40 and 50, and mammogram alone from 50.

• Risk-reducing mastectomy: usually followed by reconstruction where possible. The residual breast cancer risk afterwards is under 5%, and the survival advantage over surveillance is uncertain and appears small.

• Risk-reducing removal of the ovaries and fallopian tubes: the only proven way to lower tubo-ovarian cancer risk, not usually done before 35 because early menopause carries its own risks. Hormone replacement therapy is normally recommended afterwards unless there is a prior hormone-receptor-positive breast cancer.

• Medicines to lower risk: NICE guidance updated in 2023 says tamoxifen, raloxifene or anastrozole can be considered for people at increased breast cancer risk because of family history, weighing side effects. The benefit is clearer for BRCA2 than BRCA1.

• Men: breast screening is not recommended but breast symptom awareness is. Annual PSA screening from 40 may help detect prostate cancer in BRCA2 carriers.

• Pancreatic cancer: the UK Cancer Genetics Group does not advise screening outside research studies; the advice centres on symptom awareness and avoiding smoking.

A positive result affects more than one person. Relatives who share a parent or grandparent with the variant may each have a 1 in 2 chance of having it, and the genetics team usually helps with letters that can be passed to them. Cancer Research UK acknowledges that some relatives may not want to talk about it or may not be ready, and that a counsellor can help families find ways through this.

For people who want to avoid passing the variant on, the Human Fertilisation and Embryology Authority has approved pre-implantation genetic testing for monogenic disorders (PGT-M) for BRCA1 and BRCA2. Other routes the NHS Genomics Education Programme lists include prenatal testing, donor gametes, adoption, or conceiving naturally and testing children when they are adults.

On insurance, the NHS explains that a voluntary code agreed with the Association of British Insurers means predictive test results do not usually have to be disclosed, although insurers can still ask about family history.