Presentation: Patient with a family history of breast cancer

A 48-year-old woman presents with a breast lump and is diagnosed with a fibroadenoma. She is very concerned about her risk of breast cancer as her mother died of breast cancer at the age of 49. She is subsequently referred to the local breast service family history clinic. You are considering if genomic testing is available and appropriate for her.

Constitutional (germline) testing

Where a heritable risk factor for cancer is suspected in a family, constitutional (germline) testing is usually most informative when undertaken in a family member who has or has had a history of a relevant cancer type, as they are more likely to carry an underlying heritable genetic risk factor than a family member who has not had cancer. If a (likely) pathogenic genomic variant is found in the first person tested (proband), other relatives (with or without a previous cancer history) may then be offered predictive genomic testing.

At the present time, NHS-funded genomic testing is not usually offered to individuals that have not been affected by cancer if they have a living affected family member for whom genomic testing would be more appropriate.

In some families, where there is no living affected relative available for testing, it may be possible to start genomic testing using DNA from the tissue sample of a deceased affected relative.

If testing of tissue-derived DNA from an affected relative is not possible, testing of a close unaffected relative may be offered, if it is estimated that there is at least a 10% chance that a high-risk genomic variant explains the cancer in their affected family members.

Women with a family history of breast cancer but no personal history of breast cancer are eligible for constitutional (germline) genomic testing of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM (truncating variants and c.7271T>G only) and CHEK2 genes (truncating variants only) if they meet at least one of the following criteria:

• first-degree relative affected by breast or serous ovarian cancer;
• no living affected individual is available for genomic testing; and
• no deceased affected individual with tumour material is available for testing; and
• pathology-adjusted Manchester score ≥20 or CanRisk score ≥10% (for the unaffected relative). (These tools can be used to calculate risks. If you are not confident to do so, seek support from your local clinical genetics service.)

In this context, careful pre-test counselling and interpretation of results is required. In unaffected individuals who undergo “unaffected” germline genomic testing, a negative result does not exclude the possibility that a genetic risk factor is present in their family, and other unaffected at-risk relatives may also be eligible for genomic testing, although the likelihood of identifying a pathogenic variant may be lower in subsequent tests. A negative result in an unaffected individual does not exclude the possibility that they carry a heritable genetic risk factor for cancer that cannot be identified using current technology, for which reason enhanced cancer screening may still be recommended, guided by the family history and estimation of lifetime cancer risks after accounting for negative genomic test result.

Somatic (tumour) testing

• No somatic (tumour) testing is available for this patient, as there is no personal history of cancer.
• Testing on tumour-derived DNA would be appropriate in the scenario of a patient with a significant family history of breast cancer with a deceased affected individual from whom stored tumour material is available for testing.

• Consult the National Genomic Test Directory to ensure your patient is eligible for testing. You can also access a spreadsheet containing details of all available tests.
• For information on the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service signed-off panels resource.
• For patients with a family history of breast cancer the options are:
  • R208 (inherited breast cancer and ovarian cancer): This tests for constitutional (germline) variants in BRCA1, BRCA2, PALB2, ATM* and CHEK2* (*truncating variants only).
  • R386 (BRCA1 and BRCA2 somatic test): Where there is no living affected individual available to test, but tumour material is available from a deceased affected individual.
• A record of discussion (RoD) form is required prior to constitutional (germline) tests. If you have not completed an RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form.
• Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied to your patient’s/their family’s (if appropriate) DNA. These tests include (but are not restricted to):
  • Single gene sequencing
  • Gene panel sequencing
  • MLPA
• For DNA-based tests (all the above listed tests), an EDTA sample is required. Please refer to your local Genomics Laboratory Hub for details of test request forms and where to send samples.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Mainstreaming Cancer Genetics: BRCA toolkit
• NHS England: National Genomic Test Directory and eligibility criteria (note that somatic (tumour) tests are listed in the directory for cancer, while constitutional (germline) tests are listed in the directory for rare and inherited disease. More information is available in this article)
• NICE: Guidance on genetic testing for patients with breast and ovarian cancer

For patients

• Breast Cancer Now: ‘Family history of breast cancer: managing your risk’ booklet
• Cancer Research UK: Inherited breast cancer information
• Macmillan: Inherited breast and ovarian cancer information