Presentation: Patient with breast cancer who has had direct-to-consumer (DTC) genomic testing

A 45-year-old woman is diagnosed with localised triple-negative breast cancer. There is no significant family history of cancer. She undergoes constitutional (germline) genomic testing as per national guidance and no pathogenic variants are found in BRCA1, BRCA2 or PALB2. She undergoes mastectomy and returns to the oncology clinic to discuss adjuvant treatment. She informs you that she has had a constitutional (germline) direct-to-consumer (DTC) genomic test which shows a pathogenic variant in the BRCA1 gene.

Constitutional (germline) testing

• Women with breast cancer (primary or metastatic) or high-grade ductal carcinoma in situ are eligible for constitutional (germline) genomic testing of the 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:
  • 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 or HER2-positive breast cancer ≤35 years are also eligible for testing of TP53. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
• Consider a 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 (≥one case occurred <70 years); or
  • two cases of lobular breast cancer <50 years, such as bilateral or multiple ipsilateral tumours.

• High false positive rates have been reported for rare variants detected following analysis of raw DTC sequencing data by a third-party company. Variants identified in this manner should be validated in a clinical laboratory before any change in management is recommended. At present, however, validation of DTC results is not funded by the NHS unless the patient would otherwise meet criteria for germline genomic testing.
• Conversely, a ‘negative’ DTC test should not replace the need for formal constitutional (germline) genomic testing in those women fulfilling eligibility criteria, as many DTC tests offer testing of only certain variants in certain genes rather than full sequencing (for example, some DTC tests will check only for the three Ashkenazi Jewish founder variants in BRCA1 or BRCA2, and will not detect the thousands of other potential pathogenic variants that have been reported in these genes). 

• Do not assume that the DTC testing that has been done is complete or that the results are accurate.
• No clinical action should be taken based on results from DTC testing.
• Only results that have been obtained from a clinical diagnostic laboratory should be used to determine management or plan preventative strategies.
• In this case, as an NHS diagnostic test has already been performed, it may be helpful to contact the NHS laboratory directly to confirm that no pathogenic mutations were identified. It may provide reassurance to both you and the patient.
• 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)
• NICE: Guidance on genetic testing for patients with breast and ovarian cancer
• Science Weekly podcast: The dangers of DIY genetic testing (audio, 28 minutes)

References:

• Burton A. ‘Are we ready for direct-to-consumer genetic testing?‘. The Lancet 2015: volume 14, issue 2, pages 138–139. DOI: 10.1016/S1474-4422(15)70003-7
• Chandrasekeran D, Manchandra R. ‘Germline and somatic genetic testing in ovarian cancer patients‘. British Journal of Obstetrics and Gynaecology 2018: volume 125, issue 11, page 1,460. DOI: 10.1111/1471-0528.15171
• Edelman E, Eng C. ‘A practical guide to interpretation and clinical application of personal genomic screening‘. British Medical Journal 2009: volume 339, issue 7,730, b4253. DOI: 10.1136/bmj.b4253
• Horton R, Crawford G, Freeman L and others. ‘Direct-to-consumer genetic testing‘. British Medical Journal 2019: volume 367, issue 8,218, l5688. DOI: 10.1136/bmj.l5688
• McCartney M. ‘Direct to consumer genetic testing – is all knowledge power?‘. British Medical Journal 2015: volume 350, issue 8,000, h439. DOI: 10.1136/bmj.h439

For patients

• Science Weekly podcast: The dangers of DIY genetic testing (audio, 28 minutes)