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Example clinical scenario

A 41-year-old woman is diagnosed with a grade-three oestrogen receptor (ER)-negative, human epidermal growth factor receptor-2 (HER2)-negative, T3N1M0 left-sided breast cancer. There is a family history of breast cancer, which affected the patient’s mother at the age of 58.

When to consider genomic testing

Constitutional (germline) testing

  • Patients presenting with ER-negative, HER2-negative breast cancer are eligible for constitutional (germline) testing of the BRCA1, BRCA2, PALB2, ATM*, CHEK2*, RAD51C* and RAD51D* genes (*truncating variants and high-risk missense variants only) if they meet at least one of the following R208 test criteria:
    • Age <60 at diagnosis;
    • Ashkenazi Jewish ancestry and breast cancer at any age;
    • pathology-adjusted Manchester score ≥15 or CanRisk carrier probability of ≥10% (these tools can be used to calculate risks; if you are not confident in using them, seek support from your local clinical genetics service); and/or
    • the patient is male.
  • Patients with high-risk, ER-negative, HER2-negative early breast cancer who are known to have a constitutional (germline) BRCA variant may be eligible for adjuvant treatment with the PARP inhibitor olaparib. This has been approved by NICE for cases that meet the following eligibility criteria for the Olympia clinical trial:
    • patients with triple-negative tumour (TNT) and an incomplete pathological response to neoadjuvant chemotherapy treatment;
    • patients with TNT and axillary node-positive disease who have not received neoadjuvant chemotherapy but have undergone surgery and adjuvant chemotherapy; or
    • patients with axillary node-negative disease with an invasive primary tumour >2cm who have not received neoadjuvant chemotherapy, but have undergone surgery and adjuvant chemotherapy.
  • Women diagnosed with breast cancer who do not meet the above R208 criteria for familial breast cancer genomic testing, but have a personal diagnosis of breast cancer that would meet the criteria for adjuvant PARP inhibitor therapy, are eligible for BRCA1 or BRCA2 constitutional (germline) testing under test code R444.1.
  • Women diagnosed with breast cancer ≤30 are also eligible for testing of TP53. Testing can be taken contemporaneously (from the same sample) with testing of other genes after appropriate pre-test counselling.
  • Consider referral to clinical genetics for any woman with breast cancer (primary or metastatic) who has a personal and/or family history of endometrial, thyroid or diffuse gastric cancers, or non-cancerous features such as cleft lip or palate, macrocephaly, mucocutaneous lesions or a history of intussusception, which may be features of an underlying syndromic cause of breast cancer predisposition.
  • Patients with a negative or unknown constitutional (germline) BRCA1 or BRCA2 variant status and ER-negative, HER2-negative early breast cancer who do not have a pathological complete response to neoadjuvant chemotherapy may be recommended for adjuvant capecitabine treatment. These patients should have DPYD constitutional (germline) testing prior to commencing treatment.

Somatic (tumour) testing

  • Whole genome sequencing (WGS) for triple-negative breast cancer of any stage is currently available as a pilot study in some regions and can be requested to inform clinical trial options.
  • Somatic (tumour) testing may also be available as part of clinical trials and is likely to become more widely available in the future.

What do you need to do?

  • Consult the National Genomic Test Directory to ensure that your patient is eligible for testing. You can also consult a spreadsheet containing details of all available tests.
  • Decide which of the panels best suits the needs of your patient.
  • For constitutional (germline) testing of patients affected with ER-negative, HER2-negative early breast cancer, the options are:
    • R208 Inherited breast cancer and ovarian cancer: This tests for constitutional (germline) variants in BRCA1, BRCA2, PALB2, ATM*, CHEK2*, RAD51C* and RAD51D* (*truncating variants only);
    • R444 NICE-approved PARP inhibitor treatment: This tests the same genes as R208;
    • R216 for constitutional TP53 testing; and
    • M3.7 for DPYD testing.
  • 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 DNA. These tests include but are not restricted to:
  • A record of discussion (RoD) form is required prior to constitutional (germline) tests.
  • For DNA-based constitutional (germline) tests, an EDTA blood sample is required. Please refer to your local Genomic Laboratory Hub (GLH) for details of test request forms and where to send samples.
  • WGS for triple-negative breast cancer of any stage can be requested as code M234. WGS requires access to a fresh tumour sample and a matched bloods (EDTA) sample for constitutional (germline) testing, and a RoD form must be completed. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.
  • 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


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  • Last reviewed: 08/10/2023
  • Next review due: 30/04/2024
  • Authors: Dr Sarah Howlett
  • Reviewers: Dr Ellen Copson. Dr Terri McVeigh