Training activity information
Details
Perform variant interpretation of copy number changes and other structural variation (for example inversions and translocations) for patients referred for rare disease investigations.
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?
- How will you identify what is expected of you in relation to accurately interpreting CNVs and complex structural variations (e.g., inversions and translocations)?
- In what ways will you demonstrate proficiency in ISCN or HGVS nomenclature and assessing clinical significance for these specific rare disease variants?
- What defines a high-quality interpretation for a range of variations, including pathogenic deletions/duplications versus balanced translocations?
- How will you clarify the expected depth of interpretation and the prioritisation of ACGS or ACMG guidelines?
What is your prior experience of this activity?
- What is your existing knowledge of interpreting data from technologies such as microarrays, NGS, or karyotyping/FISH?
- What specific challenges do you anticipate, such as adjudicating variable penetrance, managing mosaic findings, or integrating data to confirm genomic orientation?
- How will you recognise the scope of your own practice, and which situations (e.g., novel rearrangements or marker chromosomes) will require you to seek senior advice?
- How would you describe your current feelings regarding the professional responsibility involved in providing results for complex rare disease cases?
What do you anticipate you will learn from the experience?
- Which specific skills do you aim to develop, such as using bioinformatic tools for structural variant analysis or mastering nomenclature for complex rearrangements?
- What insights do you hope to gain regarding genotype-phenotype correlations (e.g., dysmorphism or infertility) and their impact on family follow-up and recurrence risk?
What additional considerations do you need to make?
- How will you apply past feedback on your ability to classify variants to these specific rare disease tasks?
- What critical information, including detailed phenotype, family history, and assay limitations, must you consider before starting?
- Which current best practice guidelines for chromosomal and copy number variants are most relevant to your approach?
In action
During the activity, did anything unexpected occur?
- What surprises or deviations from your plan are you noticing while reviewing the genomic data for CNVs or structural variations?
- How are you managing small CNVs or regions of variable penetrance where clinical significance is unclear?
- How are you addressing structural rearrangements that contradict the clinical presentation or phenotype?
- In what ways are you resolving data quality issues or technical artifacts (e.g. in log R ratio or BAF plots) that obscure true genomic changes?
- How are you determining the need for immediate reflex testing (e.g. FISH or parental studies) to confirm orientation or inheritance?
- How are you adjudicating conflicting database classifications that require manual review?
How are you reacting to the unexpected development?
- How are you adapting your analysis approach in response to unexpected findings?
- How are you utilising CNV databases or parental data in real-time to clarify clinical significance?
- Which best practice guidelines (e.g. ACGS or ACMG) are you consulting to resolve structural variant ambiguity?
- How are you identifying the point where you must seek immediate senior advice for cases falling outside routine policy?
- How is the technical complexity affecting your confidence in assigning appropriate nomenclature or reaching a diagnostic conclusion?
What was the conclusion or outcome?
- How are you ensuring you are working within your scope of practice, and at what point do you recognise that a case requires senior support?
- What are you learning regarding improved workflows for technical limitations (e.g. mosaicism) or the interpretation of data metrics?
- How are your real-time decisions accounting for the potential clinical and familial implications of the findings?
On action
What happened?
- Summarise the key points of the experience, detailing the specific cases you reviewed and the types of variants interpreted, such as copy number gains/losses, inversions, or translocations.
- What were the essential details—such as a specific phenotype, a familial inheritance pattern, or a complex genomic rearrangement—that significantly influenced your interpretation?
- Include any ‘reflect-in-action’ moments where you had to adapt. For example, did you have to change your initial classification of a CNV after reviewing raw data (like log R ratios) or consulting external databases?
- Describe your feelings during the process. Did you feel confident applying ISCN or HGVS nomenclature, or did the technical complexity of a structural variant cause uncertainty?
How has this experience contributed to your developing practice?
- Identify specific learning regarding the clinical significance of structural variation in rare disease. What did you learn about applying current best practice guidelines (e.g., ACGS or ACMG) to these specific variant types?
- What strengths did you demonstrate (e.g., a systematic approach to CNV analysis)? Conversely, what knowledge gaps were evident, such as difficulty interpreting variants in regions of variable penetrance or novel balanced rearrangements?
- Compare this experience against previous interpretation tasks. Have you improved in your ability to correlate genomic findings with clinical presentation?
- Identify any challenges (e.g., technical artifacts or conflicting database evidence) and how you reacted to them. Did you need to seek advice or escalate the case to a senior scientist to ensure you were working within your scope of practice?
- Do you feel more prepared to interpret complex structural variants independently?
What will you take from the experience moving forward?
- Identify the specific actions you will take to support your learning, including how you will incorporate feedback regarding your interpretations.
- What will you do differently next time? For instance, will you use different bioinformatic tools for initial screening or change how you document the rationale for a classification?
- Do you need to practise any aspect of the activity further, such as mastering the use of specific resources for structural variant interpretation or reviewing the evidence required for reclassifying VUS?
- How will you ensure you stay up-to-date with the evolving guidelines and databases for structural variation in rare disease genomics?
Beyond action
Have you revisited the experiences?
- Have you reviewed your actions and conclusions from earlier reflections for this activity?
- Identify specific actions you previously noted were needed to improve your practice—such as mastering ISCN/HGVS nomenclature for complex translocations or refining your application of ACGS/ACMG guidelines for CNVs—and determine if you have successfully completed these.
- Are you now ready to demonstrate this new learning in practice for increasingly complex cases, such as those involving novel inversions or cryptic rearrangements?
- Has discussing a challenging structural variant in a multidisciplinary team (MDT) meeting or with a supervisor changed your perspective on how to assign clinical significance or determine the necessity of familial follow-up?
How have these experiences impacted upon current practice?
- Consider how the accumulated learning from interpreting these diverse structural changes will support you in preparing for observed ‘in-person’ assessments, such as:
- Direct Observation of Practical Skills (DOPS): e.g. ‘Classify a variant’.
- Case-based Discussions (CBDs): where you may be required to justify your interpretation of a rare disease structural variant and its clinical implications.
- How has your practice developed and evolved over time? For example, can you identify a clear improvement in your ability to correlate a patient’s clinical phenotype with specific copy number changes compared to your initial attempts?
- Are you more confident in recognising when a case is beyond your scope of practice, such as a complex marker chromosome or a finding with novel ethical implications, and knowing exactly when to escalate for senior review?
- How have the transferable skills developed here—such as clinical reasoning and diagnostic planning—informed your approach to other genomic datasets, such as identifying structural variants in Whole Genome Sequencing (WGS)?
How might these contribute to your future practice?
- As genomic technologies continue to evolve (e.g., transition to new sequencing platforms or bioinformatic tools), how will your foundational understanding of assay principles and variant interpretation help you adapt to new diagnostic algorithms?
- What clear actions for continued development have you identified to ensure you stay current with the rapidly evolving landscape of structural variation guidelines and databases?
Relevant learning outcomes
| # | Outcome |
|---|---|
| # 3 |
Outcome
Interpret genomic variants to investigate the clinical significance using appropriate nomenclature. |