The Risks and Limitations of Direct-to-Consumer Genetic Testing for Hereditary Breast Cancer

Testing for the breast cancer susceptibility genes, BRCA1 and BRCA2, is becoming increasingly popular as public awareness of hereditary breast cancer expands.

BRCA1/2 mutations are associated with significantly elevated cancer risks, including up to an 87% lifetime risk to develop female breast cancer and up to a 40% lifetime risk to develop ovarian cancer.

As such, women who test positive for BRCA mutations may elect to have risk-reducing surgeries, including bilateral mastectomy and/or bilateral salpingo-oophorectomy.

Since genetic testing results can be used to make irreversible, life-altering decisions, it is critical that patients and their healthcare providers have an accurate understanding of their hereditary cancer risk.

One option for BRCA1/2 testing is through direct-to-consumer (DTC) genetic testing, which is provided by commercial laboratories directly to consumers without requiring an order by a healthcare professional or authorization for payment by a third-party payer.

In 2018, the United States’ Federal Drug Administration (FDA) authorized DTC testing for select variants in the BRCA1 and BRCA2 genes. While this testing has the FDA’s stamp of approval, it has significant limitations and risks of which to be aware.

One significant limitation is that DTC testing is not comprehensive. It does not include evaluation of all genes implicated in a particular disease and does not detect all possible mutations within the genes analyzed.

DTC companies can evaluate for only three select mutations of more than one thousand clinically significant variants in the BRCA1/2 genes. These alterations, called founder mutations, occur frequently in the Ashkenazi Jewish (Eastern European) population, at an incidence of 1 in 40 individuals.

However, the founder mutations are not the most common BRCA mutations in the general population; most BRCA1/2 mutations associated with Hereditary Breast and Ovarian Cancer (HBOC) syndrome are not detected by DTC testing.

Moreover, BRCA1 and BRCA2 are only two of many known hereditary cancer susceptibility genes; they may account for only approximately 50% of HBOC.

It is for this reason that in a clinical setting, genetics providers routinely offer individuals with a personal or family history of breast cancer multi-gene panels, to include BRCA1/2 in addition to other genes shown to be associated with an inherited predisposition to develop breast cancer.

In summary, DTC companies provide an incomplete picture of an individual’s inherited genetic predisposition to breast cancer.

As such, consumers who receive negative results may be given a false sense of reassurance.

Another potential harm of DTC testing is the possibility of a false positive result. In fact, multiple studies have shown that a considerable proportion of mutations detected by DTC testing are not truly disease-causing (1,2).

The problem lies in the limitations of testing methodology. While clinical grade testing involves comprehensive gene analysis to evaluate for all possible mutations, many DTC labs use single nucleotide polymorphism (SNP) arrays, a method that is akin to spot checking genes at predetermined sites.

SNP arrays were initially designed to evaluate for common genetic variations in the general population. They are notoriously inaccurate when it comes to detecting or ruling out the rare genetic variants that cause disease.

Many SNP chip designs, including those used by DTC companies, have been enhanced to include certain rare pathogenic variants, such as the BRCA founder mutations. Savvy consumers, however, may request their raw data, to include thousands of additional rare variants that were assayed but not included in the DTC company’s report due to lack of quality control.

Once consumers download their raw data, they may use any of the available third-party services (which are not government regulated) to interpret their results.

When inaccurate data is entered, incorrect conclusions are generated. Therefore, it is critical that healthcare providers question the source of patients’ genetic testing results and validate any SNP chip results from DTC testing with standard diagnostic testing.

Patients with positive DTC test results should be directed to a knowledgeable healthcare provider for confirmatory testing through a CLIA-certified laboratory before medical interventions, such as risk-reducing surgeries, are considered (3).

Many of the aforementioned limitations are described by the FDA, DTC companies, and third-party interpretation services.

The problem is that many consumers don’t read the fine print.

And those who do may not understand fully the implications of the caveats. So, while the intent of DTC genetic testing may be to initiate dialogue between patients and physicians regarding hereditary cancer risk, not all patients use their results as directed.

Misapplication of DTC results can have dire consequences, including forgoing recommended cancer screening, unnecessary emotional distress, and even inappropriate medical intervention.

In conclusion, DTC testing is not a substitute for clinical-grade testing. It is recommended that patients who are interested in learning their BRCA status consult with a knowledgeable physician or genetic counselor to ensure that accurate testing is ordered.

Not only will qualified healthcare professionals make certain that reliable genetic testing is completed, but they will also interpret test results in the context of patients’ personal and family histories to establish personalized plans for cancer screening and risk reduction.

When it comes to something as serious as cancer risk prediction, genetic testing is best left in the hands of experts.

References:

1. Tandy-Connor S, Guiltinan J, Krempely K, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 2018;20(12):1515-1521. doi:10.1038/gim.2018.38

2. Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation. BMJ. 2021;372:n792. Published 2021 Mar 22. doi:10.1136/bmj.n792

3. Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, Elkhanany A, Friedman S,Goggins M, Hutton ML; CGC, Karlan BY, Khan S, Klein C, Kohlmann W; CGC, Kurian AW, Laronga C, Litton JK, Mak JS; LCGC, Menendez CS, Merajver SD, Norquist BS, OffitK, Pederson HJ, Reiser G; CGC, Senter-Jamieson L; CGC, Shannon KM, Shatsky R, Visvanathan K, Weitzel JN, Wick MJ, Wisinski KB, Yurgelun MB, Darlow SD, Dwyer MA. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021Jan 6;19(1):77-102. doi: 10.6004/jnccn.2021.0001. PMID: 33406487