Training activity information
Details
Interpret and report sequence variants
Type
Entrustable training activity (ETA)
Evidence requirements
Evidence the activity has been undertaken by the trainee repeatedly, consistently, and effectively over time, in a range of situations. This may include occasions where the trainee has not successfully achieved the outcome of the activity themselves. For example, because it was not appropriate to undertake the task in the circumstances or the trainees recognised their own limitations and sought help or advice to ensure the activity reached an appropriate conclusion.
Reflection at multiple timepoints on the trainee learning journey for this activity.
Reflective practice guidance
The guidance below is provided to support reflection at different time points, providing you with questions to aid you to reflect for this training activity. They are provided for guidance and should not be considered as a mandatory checklist. Trainees should not be expected to provide answers to each of the guidance questions listed.
Before action
What does success look like?
- Identify what is expected of you in relation to accurately interpreting and reporting sequence variants in the context of adult genomics.
- Review learning outcomes specifically related to interpreting genomic variants and interpreting and reporting genomic testing.
- Discuss with your training officer what constitutes a successful interpretation and reporting of sequence variants, considering the importance of using established guidelines for variant classification and conveying clinical significance accurately.
What is your prior experience of this activity?
- Think about what you already know about interpreting sequence variants. Have you classified variants using established guidelines (e.g., ACMG/AMP) before?
- Consider possible challenges you might face, such as interpreting novel variants, variants in genes with complex inheritance patterns, or determining the pathogenicity of missense variants. How might you handle these?
- Recognise the scope of your own practice, knowing when you will need to seek advice or help with variant interpretation, particularly for challenging cases or variants of uncertain significance, and from whom (e.g., senior scientist, variant interpretation committee).
- Acknowledge how you feel about embarking on the detailed interpretation and reporting of individual sequence variants.
What do you anticipate you will learn from the experience?
- Consider the specific skills you want to develop, drawing upon previous experiences (if any). For example, you might focus on improving your efficiency in using bioinformatic tools and databases or refining your application of classification rules.
- Identify the specific insights you hope to gain, perhaps a deeper understanding of the evidence required to classify variants at different levels (e.g., pathogenic, VUS) or the challenges of interpreting variants in genes associated with variable phenotypes.
What additional considerations do you need to make?
- Consult any actions you identified following previous experiences, perhaps from prior variant interpretation or reporting activities.
- Identify important information you need to consider before embarking on the activity. This might include reviewing variant interpretation guidelines, familiarising yourself with relevant databases and resources, and understanding the specific phenotype of the patient whose variants you are interpreting.
In action
Is anything unexpected occurring?
- Are you noticing anything surprising or different from what you anticipate while interpreting and reporting this specific sequence variant?
- Are you encountering situations such as:
- A sequence variant with conflicting classifications (e.g., listed as benign in one database but VUS in another), requiring careful manual adjudication?
- Difficulty applying guidelines (e.g., ACMG/AMP) due to ambiguous functional data or limited segregation evidence for a specific rare variant?
- The variant being located in a genomic region with complex regulatory elements, making it difficult to predict the functional effect based solely on sequence data?
- How is this experience comparing with previous experiences of similar activities?
How are you reacting to the unexpected development?
- How is this impacting your actions? Did you adapt or change your application of classification rules in the moment?
- Consider the steps you are taking in the moment, such as:
- Immediately checking additional variant databases or consulting recent literature to gather more evidence for a variant with unclear clinical significance.
- Focusing on secondary sources e.g., splice prediction tools, conservation scores to gain immediate insight into the predicted biological impact of the sequence variant.
- Discussing the interpretation of a complex or novel sequence variant with a molecular pathologist or clinical geneticist.
- How are you feeling in that moment? Is the complexity affecting your confidence in classifying the variant (e.g., as pathogenic or VUS)? Are you finding it difficult to adapt your methodology to integrate data from different functional studies? Do you feel positive you can reach a successful conclusion?
What is the conclusion or outcome?
- Identify how you are working within your scope of practice when interpreting the variant e.g., successfully classifying a variant of uncertain significance, but clearly documenting all evidence used to support that classification.
- What are you learning as a result of the unexpected development? For example, are you gaining key learning about refining your criteria application for classifying missense variants, or improving your efficiency in using bioinformatic tools and databases for complex variants?
On action
What happened?
- Begin by summarising the key points of the experience, detailing the types of sequence variants you interpreted and reported e.g., single nucleotide variants, small insertions/deletions.
- Identify the resources or guidelines you specifically used to classify the clinical significance of these variants.
- Were there any variants that were particularly challenging to interpret or classify (e.g., VUS or complex variants)?
- Reflect on any specific feelings (e.g., uncertainty, confidence) experienced during the variant interpretation process.
How has this experience contributed to your developing practice?
- Identify what learning you can take from this experience. What skills or knowledge did you develop or improve in interpreting and reporting sequence variants according to best practice guidelines (e.g., utilising bioinformatic tools and databases)?
- How does your variant interpretation practice compare to previous experiences? Has your ability to apply classification criteria improved?
- Were you able to overcome challenges encountered during variant interpretation, such as conflicting classification evidence?
- What strengths or knowledge gaps were evident during the interpretation process?
What will you take from the experience moving forward?
- Identify the actions or ‘next steps’ you will now take to support the assimilation of what you have learned, you could include feedback you have received on your reports for sequence variants.
- How will you ensure accuracy, consistency, and adherence to current guidelines in your variant interpretation and reporting? What will you do differently next time, perhaps ensuring you consult national variant meetings or curation tools?
- What areas for continued development have been identified in your ability to interpret and report sequence variants? Do you need to practise any aspect further, such as refining the application of specific classification rules?
Beyond action
Have you revisited the experiences?
- Revisit the sequence variants you interpreted and reported on for this activity. Evaluate and re-evaluate your interpretation process and classification.
- Compare your current approach to interpreting and reporting sequence variants with how you initially approached it. How has your understanding of variant classification according to best practice guidelines evolved?
- Have you encountered challenging variants, such as variants of uncertain significance (VUS) or complex alleles, that have refined your interpretation skills e.g., using more sophisticated bioinformatic evidence? Have you completed the actions identified in previous reflections to improve your variant interpretation practice?
How have these experiences impacted upon current practice?
- How has gaining more experience in interpreting genomic variants using bioinformatic tools influenced your confidence and proficiency in this task?
- How have the interpretation and reporting skills developed here been transferable to your interpretation and reporting of other types of genetic variants or in different clinical contexts (e.g., interpreting structural variants)?
- How does the accumulated learning from this activity support your preparation for observed ‘in-person’ assessments, such as a DOPS titled ‘Classify a variant’?
- As new variants and genes associated with adult-onset disorders are discovered, and guidelines evolve, how will your foundational interpretation and reporting skills prepare you to interpret and integrate increasingly complex datasets and new information?
- What ongoing steps will you take to stay proficient in variant interpretation and classification?
Relevant learning outcomes
| # | Outcome |
|---|---|
| # 4 |
Outcome
Interpret genomic variants, including copy number and structural changes and investigate the clinical significance of variants using bioinformatic tools using best practice guidelines. |
| # 5 |
Outcome
Interpret and report genomic testing relevant to adult-onset disorders, including appropriate recommendations for patient management. |