PHG commentary: ACMG statement on clinical application of polygenic risk scores

Laura Blackburn

24 March 2023


The American College of Medical Genetics (ACMG), the organisation representing the clinical genetics profession in the US, has released three ‘points to consider’ documents in relation to polygenic scores. These come at a time when there is increased interest in the use of PRS in a range of clinical situations. The statements aim to provide guidance on the challenges and limitations of PRS for healthcare providers, considerations from a laboratory perspective and issues related to prenatal applications of PRS testing

Polygenic (risk) scores and health

Polygenic scores aim to measure the cumulative effect of multiple genetic variants to make predictions about a person’s health. The most likely areas of potential use are in risk prediction, including risk of developing a disease, disease progression and severity or prognosis. With this information, it is hoped individuals can be helped to make more informed choices about their health. It could also support clinical decision making, such as which treatment approach is most suitable for a patient.

At PHG Foundation, we have had an interest in polygenic scores for a number of years, and it is reassuring to see that the points raised in the ACMG statement confirm many of the conclusions that we have reached.

Points to consider in relation to clinical application of polygenic risk scores

Eight points are raised for consideration in relation to clinical application of PRS. These broadly cover patient engagement with testing, the implications of using testing, including in different populations, and clinical management and follow-up. It emphasises that these scores are not diagnostic, and only provide a prediction of level of risk. Therefore, a low polygenic score does not mean that an individual is not at risk of getting a disease in the future; conversely those with a high score might never get a disease. These two points highlight a challenge around the communication of risk by healthcare providers, particularly to patients and the public, including the understanding of that risk and the potential impact of the test result on patient behaviour. Both of these are areas where extensive engagement and guidance are needed. Indeed, another of the points emphasises the importance of these discussions between patient and healthcare provider.

The ACMG also points to clinical circumstances in which polygenic scores are not appropriate. One of these is where a disease has a known monogenic (single gene) cause. As we discuss in our report on polygenic scores and cancer, an example would be breast cancer caused by variants in BRCA 1 and BRCA2. In these cases, a polygenic score would not be an appropriate substitute for a genetic test examining the BRCA genes. However, there is some evidence PGS could be used to help ‘fine-tune’ the understanding of risk in women with familial breast cancer and refining treatment – offering more invasive treatment to those at the higher end of the risk spectrum, for example. The ACMG are also clear that use of these scores is not appropriate and should not be offered in the context of reproductive applications such as preimplantation embryo selection.

An important issue, covered in another of the ACMG points, is that the genetic data used to develop PRS can come from a population which is different in terms of genetic ancestry to the population in which the test might be used. Lack of diversity in genomics is a known problem and initiatives are underway to deliver genomic datasets that adequately represent the global population.

The ACMG has provided a useful and timely reminder, and much needed clarity, that there is some way to go before polygenic scores can be used routinely in healthcare.

Laura Blackburn

Promise, but more evidence needed

In our report on polygenic scores in cardiovascular disease, we concluded that, while there is promise, this is an area under development. In CVD and other diseases, including cancer, there is not yet enough evidence to support the use of polygenic scores in patient care, a point reiterated, by the ACMG.

When it comes to implementing polygenic scores into routine healthcare, there are many questions yet to be answered - how polygenic scores are going to be used, is the intention to use them for all conditions or just specific ones, are they to answer questions around diagnosis or prediction? Or both? Only when answers to these and similar questions have been articulated can robust standards for evidence generation and assessment be developed. Currently this is an issue due to a lack of clarity in describing PGS as a biomarker and how processes to calculate a PGS can be conceptualised as a test.

One size does not fit all

Polygenic scores are not a ‘one size fits all’ test and much evidence gathering is still needed to support the evaluation of PRS and to demonstrate clinical usefulness. This evidence will have to be gathered on a case by case basis since the use of polygenic scores in disease management will be very specific to the disease and the clinical context. There is also quite a lot of variety in the products that provide a polygenic score. The ACMG has provided a useful and timely reminder, and much needed clarity, that there is some way to go before polygenic scores can be used routinely in healthcare.

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