Best Practice

Best practice guidelines are developed by the genetics community to help laboratories operate to the same standards of service. They are developed and updated through the Clinical Molecular Genetics Society (CMGS). NGRL Manchester has provided support in developing guidelines and inputs to guideline updating alongside other diagnostic laboratories in the UK and internationally.

We continuously update and develop existing guidelines, in particular the guidelines for unclassified variants (UVs) which were published in 2008.

One particular area of concern is the use of multiple species alignments of amino-acid sequences. These are used to investigate the variability at a particular position in a gene and form the input data to some of the in-silico tools that have been developed to predict the effects of missense variants. The best practice guidelines recommend an approach to species alignments based on work at the International Agency for Research on Cancer (IARC) in Lyon for BRCA1 and 2 genes. We are investigating what hurdles need to be overcome in order to apply this approach to other genes. Meanwhile, we will develop a project to establish species alignments for genes tested in the UK, to provide these to laboratories, and provide detailed guidance and training in their correct use.

Best Practice Guidelines for Unclassified Variants

Unclassified variants are a continuing problem for diagnostic laboratories: in many cases laboratories are not able to determine the pathogenicity of a variant and have to issue an inconclusive report. Best practice guidelines aim to ensure that the methods and strategies available to laboratories help them to reach a conclusion and to apply the methods uniformly and correctly.

NGRL Manchester facilitated the production of guidelines for unclassified variants in 2007 with the CMGS and the Dutch Society of Clinical Genetic Laboratory Specialists (VKGL). Guidelines were drawn up following a two-day best practice workshop with members from both Societies. These are supported by the Diagnostic Mutation Database (DMuDB), bioinformatics training and species alignment applications.

Three areas of concern with the UV guidelines are that laboratory staff are not familiar with the techniques and tools described, that tools are used inconsistently and that outcomes of the recommended analyses can remain inconclusive. We are helping with the first and second points through the training courses described in the informatics section above, and we recognise that further support and guidance are required to aid consistent use of tools. Thirdly, we recognise that some of the techniques are insufficiently developed and understood to allow firm conclusions to be drawn.