Making sense of genomic variants

By Sobia Raza

25 June 2017


The aim of clinical genome analysis is to identify variants in the genome that relate to and potentially diagnose a patient’s condition. Given that the average human genome varies at more than 3 million locations, getting this analysis right is no easy task. Variant interpretation and classification is a critical step, and arguably the most complex, in the clinical analysis of genomic data.

Typically, for rare diseases, genomic var iants are categorised into one of five groups ranging from those that are definitively pathogenic (disease causing) to those that are known to be benign (having no impact on health).  Advances in genomic technology have led to an increase in the number of novel variants and genes being analysed, highlighting the need to review the variant interpretation and classification process to ensure accuracy and maximise consistency within and between genetic testing centres.

Accurate interpretation is integral to the delivery of safe and high-quality diagnostic genomics services, since incorrect classifications may result in misdiagnosis and inappropriate care. Consistency is also key, as conflicting variant classifications across different testing services could result in different clinical management decisions for patients with the same genomic variant, even from the same families. This might range from no medical intervention in one case, to a life-altering intervention in another.

Variant classification workshop

In November 2016, the UK clinical genetics and genomics community, comprising members of the Association for Clinical Genomic Science (ACGS) and the British Society for Genetic Medicine (BSGM), convened a meeting to discuss guidelines for the interpretation and classification of genomic variants in the context of rare diseases and familial cancers. The key themes arising at this meeting are summarised in a new report,Variant classification and interpretation, published by PHG Foundation and free to download here.

The main outcome of the meeting was agreement that the UK should adopt the guidelines jointly published by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) for variant interpretation. These guidelines were developed to enable a more systematic approach to variant interpretation and ultimately improve the consistency and concordance of variant classifications between clinical genetic laboratories.

Since their publication, the ACMG guidelines have been widely adopted in the US and by many European centres. They are also being integrated into a range of commercial analysis platforms. The use of a common framework to interpret variants is a positive step towards promoting international consistency which in turn facilitates the exchange of variant classifications and collaboration between international disease and gene experts to diagnose rare genetic diseases.

Power in numbers?

The November workshop provided an opportunity for professionals to share their experience of applying the ACMG guidelines so far. Early adopters conveyed that the ACMG guidelines are a constructive and objective framework for interpreting variants, but stressed the importance of applying professional judgement as necessary, especially disease / gene based expertise. Delegates also considered how potential challenges to implementing the guidelines might be addressed. Considerations included how to catalyse adoption of the guidelines through training; obtaining sufficient levels of clinical and phenotypic data to inform the variant interpretations; and processes for refinement of the guidelines. There was specific discussion as to how the guidelines might be enhanced to further support clinical practice in the UK by adding dimensions to unify the practice of laboratory and clinical medicine. 

The workshop and subsequent process for supporting the ACMG guideline adoption in the UK is an outstanding example of the way in which coordinated and collaborative efforts of a professional community can have a significant impact on quality improvement in healthcare delivery.

Since the meeting several actions have been progressed:

  • The release of a consensus statement in November 2016 by the ACGS and the BSGM recommending the UK adoption of the ACMG guidelines.
  • A training event with representatives across all 24 regional genetics centres was held earlier this year, with follow-on monthly teleconferences.
  • The ACGS have drafted UK Best Practice Guidelines for Variant Classification to describe the application of the ACMG framework in the context of UK clinical services.
  • Tools to support the application of the guidelines are also available including the recent releases of the DECIPHER variant database which now has a structured approach for recording the evidence criteria listed in the ACMG system.

Data sharing – another key to collaboration 

Such a co-ordinated and collaborative approach is essential to enabling the accurate and consistent use of the guidelines across and within laboratories. Another crucial aspect in this respect is the ability of clinical genomic centres to share variant classification decisions between them. By sharing these variant classifications, laboratories can learn whether the variant of interest has been seen before, and if so, whether it was classified in the same way. Where classifications differ or where the role of variant is uncertain, laboratories can pool their expertise and knowledge to resolve these cases and in doing so ensure that collectively they are providing the best possible services and care to patients. Studies in the US have demonstrated that the use of common guidelines and data sharing across laboratories helps to identify and resolve disparities in variant classifications. Indeed, the necessity of data sharing across NHS clinical genetic services for clinical care is clearly acknowledged, however there are continuing challenges to achieving this as outlined in the PHG Foundation report Data sharing to support clinical genetic and genomic services.

 The bottom line

Ultimately, it is crucial that these challenges are addressed, in order to ensure that developments in genomic testing are translated into better, safer care for patients and families. 

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