Diagnostic Sequencing —
Training activity: 6

Details

Identify and interpret the consequence of a genomic variant

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.

Considerations

• Genomic architecture e.g., introns, exons, promoters, UTRs, splice sites and alternative transcripts
• Different types of variation e.g., missense, splicing, loss of function, gain of function, start loss, stop loss, nonsense mediated decay and multi-nucleotide
• Interpretation of variant effects
• Consequence on disease e,g., progression, treatment, penetrance etc.
• Best practice guidelines
• Storage of data in appropriate formats according to local and national standards, taking into consideration patient confidentiality
• Implications for the patient

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 is the objective of correctly identifying a genomic variant and interpreting its consequence, including its potential impact on function and disease? What depth of interpretation is required, what resources are to be used (e.g., protein prediction tools, literature databases), and how should patient context (family, ancestry, medical history) be considered?
• Have you interpreted variant consequences before, and are you familiar with concepts like protein domain disruption, splicing effects, or regulatory element changes? What possible challenges might you face e.g. interpreting variants in non-coding regions? Dealing with complex variants, conflicting evidence, or integrating clinical information with genomic findings? How might you handle the challenges? What are the limitations of your current knowledge, and when would you need to seek advice or escalate complex cases? How do you feel about interpreting genomic variant consequences?
• What specific skills do you want to develop e.g. improving your ability to use specific interpretation tools? Your understanding of how different variant types affect protein function or gene expression? Your skill in integrating diverse data sources? What specific insights do you hope to gain e.g. a deeper understanding of molecular mechanisms by which variants cause disease? Appreciating the complexity of clinical variant interpretation? Understanding the impact of this analysis on patient care by reflecting on relevant clinical experiences? Have you reviewed any notes from previous variant interpretations, particularly where challenges were encountered or areas for further learning were identified? What important information do you need to consider before embarking on the activity, such as ensuring you have all relevant patient information (phenotype, family history, ethnicity) and access to necessary interpretation tools, databases, and current literature, and considering the specific disease context (inherited/acquired)?

In action

• As you are identifying and interpreting variant consequences, make a note of anything that feels surprising or different from what you anticipate. For example, does a seemingly benign variant unexpectedly have strong clinical evidence of pathogenicity, do two key stakeholders provide contradictory interpretations for the same variant, or does integrating patient context prove unexpectedly complex? Consider how this experience compares with previous experiences of similar activities, such as other variant interpretation tasks. Does it feel more or less familiar, especially concerning the integration of diverse data types?

• Identify how any unexpected developments, such as contradictory evidence or complex patient data, impact your immediate actions. Do you immediately ask clarifying questions about patient history, consult additional literature, or seek expert opinion from a Genomic Scientist? Do you adapt or change your interpretation approach or strategy as a result? For instance, do you shift your focus to a different type of evidence, or modify your strategy for integrating clinical and genomic findings? Do you find it difficult to adapt your interpretation style when faced with ambiguity? Does it affect your confidence in eliciting accurate interpretations? Do you feel positive you can reach a successful conclusion?

• Do you recognise when you might need to seek immediate advice or help, such as when a variant’s clinical significance is beyond your current understanding or when a complex ethical consideration arises? Identify what you learn as a result of the unexpected development. For instance, do you learn a new approach for interpreting variants in non-coding regions, a specific method for reconciling conflicting evidence, or a better way to structure your interpretation report?

On action

• Summarise the key steps involved in identifying and interpreting the consequence of the genomic variant(s). Describe the variant(s) you worked on and the methods or tools used to determine their potential consequence (e.g., on protein function). Detail the resources (like databases or guidelines) you used to support your interpretation. Were there any specific events, actions, or interactions that felt important during the interpretation process?
• What specific learning can you take from this interpretation task? For example, what strengths did you demonstrate in applying interpretation guidelines or understanding variant types like SNVs vs structural variants? What skills or knowledge gaps were evident regarding specific interpretation criteria or complex variant types? How did this experience compare against previous times you have interpreted genomic variants? Were any previous actions for development in this area achieved? Do you feel your practice has improved? Identify any challenges you experienced, such as interpreting variants with limited evidence, understanding conflicting data, or determining pathogenicity, and how you reacted to them. Did these challenges affect your ability to deal with the situation? Were you able to overcome them? Was there anything significant about this activity, such as needing to seek advice or clarification on a difficult interpretation, or ensuring you were working within your scope of practice?
• Identify the specific actions or ‘next steps’ you will take based on this experience to support your learning. What will you do differently next time you identify or interpret a genomic variant? Has anything changed in terms of what you would do if faced with a similar situation again? Do you need to practice applying specific interpretation guidelines, using certain databases, or interpreting particular types of variants further?
• How will you assimilate any feedback you received on your variant interpretation?

Beyond action

• Think back on the various variants you have identified and interpreted. Have you reviewed your reflections, particularly on interpretations that were difficult or required significant investigation? What actions did you previously commit to taking to enhance your interpretation skills, such as studying specific gene-disease relationships, practising applying interpretation guidelines, or seeking expert feedback? Have you followed through on those actions? Are you ready to demonstrate a more robust and consistent approach to variant interpretation based on your experiences and the actions you’ve taken? Has professional storytelling about challenging variant interpretations with colleagues provided new perspectives or approaches that influence your current practice?

• How has interpreting a range of genomic variants over time improved your ability to understand their likely consequence? Do you feel more confident in weighing different lines of evidence? How does your cumulative experience in identifying and interpreting variants prepare you for assessments such as interpreting a variant in a clinical context or presenting variant interpretation findings? Based on your practice, are you better able to recognise situations where interpreting a variant is beyond your current level of expertise and requires consultation or escalation?

Relevant learning outcomes

#	Outcome
# 1	Outcome Explain the structure of the human genome and the impact of variation on human development, health, and disease.
# 2	Outcome Evaluate sources of information about variation in the human genome including access, application and clinical impact.
# 3	Outcome Select appropriate tools for next generation sequencing (NGS) analysis of inherited and acquired disease.
# 4	Outcome Analyse NGS data in a clinical setting applying appropriate quality control and data validation.
# 5	Outcome Interpret and analyse various types of variants from single nucleotide variants (SNVs), through to large structural variants.