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Example clinical scenario

A 42-year-old woman is diagnosed with a grade 3 ER-negative, PR-negative and HER2-negative breast cancer. There is no evidence of metastatic disease. The patient has no significant family history of cancer. You wish to undertake genomic testing and are considering what  constitutional (germline) and/or somatic (tumour) genomic testing is available and appropriate for her.

When to consider genomic testing

Constitutional (germline) testing

  • Women with breast cancer (primary or metastatic) are eligible for constitutional (germline) genetic testing of the BRCA1BRCA2PALB2ATM* and CHEK2* genes (*truncating variants only) if they meet at least one of the following criteria:
    • triple-negative breast cancer diagnosed <60 years;
    • breast cancer (grade 2 or higher) diagnosed <40 years;
    • bilateral breast cancer and both cancers diagnosed <50 years;
    • breast cancer diagnosed <45 years and a first-degree relative (FDR) with breast cancer <45 years;
    • Ashkenazi Jewish ancestry and breast cancer at any age; or
    • pathology-adjusted Manchester score ≥15 or CanRisk carrier probability of ≥10%. (These tools can be used to calculate risks. If you are not confident to do so, seek support from your local clinical genetics service.)
  • Women diagnosed with breast cancer ≤30 years are also eligible for testing of TP53. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
  • PARP inhibitors have been licensed in Europe for second-line treatment of metastatic triple-negative breast cancer with an underlying germline pathogenic variant in BRCA1/BRCA2 but have not yet been approved by NICE for use in the NHS. They may be available in the context of clinical trials.
  • 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, diffuse gastric cancers or non-cancerous features, such as cleft lip/palate, macrocephaly, mucocutaneous lesions or a history of intussusception, which may be features of an underlying syndromic cause of breast cancer predisposition.
  • Women with lobular breast cancer may be eligible for CDH1 testing if they meet one of the following criteria:
    • lobular breast cancer <70 years and diffuse gastric cancer <70 years
    • lobular breast cancer and ≥FDR/SDR has diffuse gastric cancer (≥ 1 case occurred < 70 years); or
    • two cases of lobular breast cancer<50 years, such as bilateral or multiple ipsilateral tumours.

Somatic (tumour) testing

  • Somatic testing of ER-negative primary breast cancers is currently not routinely available.
  • Selected ER-positive, HER2-negative, lymph node-negative breast cancers with an intermediate risk of distant recurrence (using a validated tool such as Predict or the Nottingham prognostic index) are eligible for tumour profile testing (such as Oncotype DX, Prosignia, Endopredict) to inform discussions about adjuvant chemotherapy.
  • Other somatic testing for primary breast cancer may be available within clinical trials.
  • In the future, somatic testing is likely to be available and expanded to include larger somatic gene panels. Ultimately, paired somatic and constitutional whole genome sequencing (WGS) will be performed.
  • WGS for triple negative breast cancer of any stage may be available within the NHS as part of a pilot study.

What do you need to do?

  • Consult the National Genomic Test Directory eligibility criteria to ensure your patient is eligible for testing. You can also refer to this spreadsheet 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 germline testing of patients affected with breast cancer, the panel to request is:
    • R208 (inherited breast cancer and ovarian cancer): This tests for constitutional (germline) mutations in BRCA1BRCA2PALB2, ATM* and CHEK2* (*truncating variants only).
    • Women diagnosed with breast cancer <30 years, or women <35 with triple-positive (ER+,PgR+, HER2+) breast cancer are also eligible for TP53 testing (R216) after appropriate counselling.
  • 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):
  • For DNA-based constitutional (germline) tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomics Laboratory Hub (GLH) for details of test request forms and where to send samples.
  • For tumour profile tests of ER-positive, HER2-negative breast cancers, liaise with your local cellular pathology department to confirm local contract and request arrangements.
  • WGS for triple-negative breast cancer of any stage (pilot study) can be requested as code M234. WGS requires access to a fresh tumour sample and a matched blood (EDTA) sample for germline testing. An RoD must be completed for this investigation – see how to complete an RoD form. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.


For clinicians

Tagged: Breast cancer

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  • Last reviewed: 04/05/2022
  • Next review due: 04/05/2023
  • Authors: Dr Ellen Copson
  • Reviewers: Professor Kate Tatton-Brown