top of page

Genetic Testing for Breast Cancer Patients: Current guidelines, pit falls and the BRCA-DIRECT study

October is Breast Cancer Awareness Month. Here we look at the importance of BRCA and PALB2 genes, current guidelines and pit falls for genetic testing in breast cancer patients, and how the BRCA-DIRECT study is seeking to set the way for future expansion.



BRCA1, BRCA2 and PALB2 proteins are vital in preserving the breast cells normal growth. Heritable (germline) faults in these genes (known as pathogenic variants or mutations) account for about 3% of all breast cancers and about 18% of ovarian cancers.

People who carry pathogenic variants in BRCA1 have an increased lifetime risk of developing cancer: ~70% for breast and ~44% for ovarian cancer. For BRCA2, the risks are ~70% for breast and ~18% for ovarian cancer. By way of comparison, in the general population, the lifetime risk of breast cancer is ~12% and of ovarian cancer is ~1-2% [1,2,3].

However, additional genes are also involved in conferring elevated heritable risk of these cancers:

  • The frequency of pathogenic variants (mutations) in PALB2 is much lower in the population than that of BRCA1/BRCA2. Pathogenic variants in PALB2 are associated with a more modest risk of breast cancer (44% lifetime risk), whilst association between PALB2 and ovarian cancer is unclear but the risk elevation is at most small.

  • Several other genes have been associated with breast cancer susceptibility (ATM, CHEK2, TP53) and ovarian cancer (BRIP1, RAD51C, RAD51D), but for these genes the frequency of pathogenic variants and/or associated risks are substantially lower than for BRCA1/BRCA2/PALB2 [4].

  • Pathogenic variants in PALB2 and BRCA2 also confer increased risk of pancreatic cancer, and prostate cancer for BRCA2.

Why is germline genetic testing in breast cancer useful?

Identification of a BRCA1/BRCA2/PALB2 pathogenic variant in a woman with a new diagnosis of breast cancer is useful for three reasons:

  1. It may influence the type of chemotherapy that is given; platinum is often used as first-line in women with BRCA1/BRCA2 pathogenic variants.

  2. It informs her of a high risk of second breast cancer and ovarian cancer. She may choose bilateral mastectomy instead of local breast surgery.

  3. Her family can undergo testing for the pathogenic variant. They can then access high intensity screening and/or preventative surgery if they carry the pathogenic variant. Or be reassured if they don’t.

Eligibility for Genetic Testing

Current UK guidelines recommend genetic testing in women with breast cancer for whom the individual and family history score sufficiently high on carrier probability models, such as the Manchester Scoring System or BOADICEA. Currently the threshold for test eligibility equates to a 10% likelihood of detection of a pathogenic variant in BRCA1/BRCA2/PALB2, as per NICE Guidelines [5].

However, these thresholds mean that many patients/families carrying a pathogenic variant in BRCA1/BRCA2/PALB2 are ineligible for testing. In particular, families that (1) are small (2) have a preponderance of males (3) in which people have been adopted or died young, or (4) those which have, by chance, fewer than the requisite number of cancer cases.

In addition, operational, logistic and socio-economic issues mean that even more families fail to access genetic testing. A recent study in London found that less than 3% of carriers of BRCA1/BRCA2 pathogenic variants have been identified to date and, if we maintain our current approaches to genetic testing, it will be more than 100 years until the majority are identified.

Blocks to Genetic testing

Historically, genetic tests were ‘rationed’ on account of the laboratory processes for BRCA-testing being very expensive and arduous. A revolution in sequencing technologies has meant that the cost and speed of genetic testing have improved dramatically.

Instead, what is cost- and rate-limiting for expansion of genetic testing is the broader infrastructure around delivery: the manpower, capacity and cost of arranging and delivering the appointments for genetic counselling and return of results.


Funded by CRUK and led by Prof. Clare Turnbull, we are in process of developing the BRCA-DIRECT study, for which recruitment will commence in summer 2021 at the Royal Marsden (London, UK) and hospitals in Manchester (UK).

Through this study, we will:

  • Offer testing for BRCA1/BRCA2/PALB2 to all women diagnosed with breast cancer.

  • Compare delivery of pre-test information on genetic testing via a digital interface compared to 1:1 counselling with a genetic counsellor.

  • Testing will be performed on a saliva sample collected at the breast cancer clinic.

  • Compare patient anxiety, knowledge and satisfaction between the two approaches.

If the digital approach is demonstrated by this study to be non-inferior, this could open up opportunity for dramatic expansion of genetic testing at time of cancer diagnosis. Not only will this inform patients regarding their future risk of other cancers, but if performed promptly and rapidly, will help guide the best surgery and chemotherapy with which to treat their recently-diagnosed cancer.


Projects such as BRCA-DIRECT are essential to catalyse change in how genetic testing is delivered to patients, along with related projects, such as our CRUK-funded program CanGene-CanVar, in which we are developing clinician and patient-facing materials to support estimation and communication of risk for the variants in cancer susceptibility genes when detected.



bottom of page