Rare Disease 1 —
Training activity: 2

Details

Perform interpretation of sequence variants for patients referred for investigation of rare disease and make recommendations for further testing required to reclassify variants, to include:

• missense,
• nonsense,
• splice site,
• indels
• frameshifts.

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 and reporting sequence variants for rare disease cases?
• In what ways will you demonstrate proficiency in using appropriate nomenclature and interpreting the clinical significance for specific variant types, including missense, nonsense, splice site, indels, and frameshifts?
• What constitutes a successful recommendation for further testing, and how will you identify which specific evidence (e.g., parental segregation or functional assays) is needed to potentially reclassify a variant?
• How will you gain clarity on the expected level of interpretative detail and the local standards for making testing recommendations?

What is your prior experience of this activity?

• What do you already know about interpreting sequence variants, and have you previously classified variants using established guidelines, such as ACMG/AMP, for other modules or cases?
• What specific challenges do you anticipate encountering, such as interpreting novel variants, assessing the pathogenicity of missense variants with conflicting predictions, or navigating complex inheritance patterns?
• How will you recognise the scope of your own practice for this activity, and in what situations—such as a challenging VUS or a variant in a gene with limited clinical data—will you need to seek advice and from whom?
• How would you describe your current feelings regarding embarking on the detailed interpretation of these diverse variant types without direct supervision?

What do you anticipate you will learn from the experience?

• Which specific skills do you want to develop, such as improving your efficiency in using bioinformatic tools and databases or refining your application of specific classification rules for splice site or frameshift variants?
• What specific insights do you hope to gain regarding the evidence required for reclassification, specifically in determining when a functional or family study is likely to provide enough evidence to move a variant from VUS to Likely Pathogenic?

What additional considerations do you need to make?

• How will you consult actions identified following previous experiences of variant interpretation or reporting to ensure you apply that feedback to these rare disease cases?
• Which specific information sources—including the patient’s phenotype and relevant clinical guidelines for the suspected disorder—must you consider before embarking on the activity?
• How will you review the limitations of current assay methodologies to ensure your recommendations for further testing are both technically feasible and clinically appropriate?

In action

During the activity, is anything unexpected occurring?

• What are you noticing that is surprising or different from your initial plan as you interpret these specific sequence variants (missense, nonsense, splice site, indels, and frameshifts)?
• How are you adjudicating conflicting database classifications (e.g. benign vs. VUS) for identified sequence variants?
• In what ways are you managing difficulties applying ACMG/AMP guidelines when functional or segregation data is ambiguous?
• How are you evaluating variants in complex regulatory regions where functional effects are difficult to predict from sequence data alone?
• How are you resolving complex or contradictory recommendations for follow-up testing (e.g. segregation or functional assays) for the suspected rare disease?
• How does this specific interpretation task compare with your previous experiences of variant classification in terms of complexity and data integration?

How are you reacting to the unexpected development?

• How is this unexpected development impacting your actions in the moment, and are you adapting your approach to variant filtering or evidence gathering appropriately?
• How are you utilising additional variant databases or recent literature in real-time to gather evidence for variants with unclear significance?
• Which alternative analysis strategies, such as splice prediction tools or conservation scores, are you employing to gain deeper insight into the variant’s biological impact?
• How are you identifying the specific point where you must seek immediate advice from a senior specialist regarding a complex or novel variant?
• How are you feeling in that moment? Is the technical complexity affecting your confidence in assigning a final classification (e.g., Pathogenic vs. VUS), or are you finding it difficult to integrate data from disparate functional studies?

What is the conclusion or outcome?

• How are you ensuring you are working within your scope of practice as you manage the interpretation challenge, for example, by successfully classifying a VUS while clearly documenting all evidence used to support that classification?
• What are you learning in real-time as a result of the unexpected development, such as mastering a new technique for refining classification rules for specific variant types (like frameshifts or splice sites)?
• In what ways are you ensuring that your final interpretation and recommendations for further testing (e.g., reclassification strategies) consider the potential implications for the patient and their family?

On action

What happened?

• Summarise the key points of the experience, detailing the specific rare disease cases you reviewed and the types of sequence variants you interpreted (e.g., missense, nonsense, splice site, indels, or frameshifts).
• Which resources or guidelines (e.g., ACMG/AMP, ClinVar, or specific rare disease databases) did you use to classify the clinical significance of these variants?
• What specific events or interactions that felt important, such as justifying a recommendation for further testing (e.g., segregation analysis or functional studies) to reclassify a variant?
• Include any ‘reflect-in-action’ moments where you had to adapt, for instance, how did you handle a variant with conflicting classifications in different databases or a finding that required manual adjudication?
• How did you feel during the process? Did you feel confident in your final classifications, or did certain variant types (like complex indels or splice site variants) cause uncertainty?

How has this experience contributed to your developing practice?

• What strengths did you demonstrate in applying variant classification rules? Conversely, what knowledge gaps were evident—perhaps in using specific bioinformatic tools or interpreting variants in genes with complex regulatory elements?
• Have you improved in your ability to synthesise evidence into a coherent reclassification recommendation?
• How did you react to challenges, such as variants with limited clinical data? Were you able to overcome these hurdles, and how did your reaction impact the outcome for the case?
• Did you need to seek advice or escalate the case to a senior clinical scientist or a variant interpretation committee to ensure you were working within your scope of practice?
• Do you feel more prepared to interpret rare disease variants independently in the future?

What will you take from the experience moving forward?

• Identify the ‘next steps’ you will take to support your learning. For example, will you seek out more cases involving splice site prediction or practice using specific curation tools?
• What will you do differently next time you encounter a Variant of Uncertain Significance (VUS) that requires a reclassification plan?
• How will you incorporate any feedback received regarding your ability to accurately apply nomenclature and clinical evidence?
• Do you need further practice in specific areas, such as attending national variant meetings or refining your application of specific ACMG classification rules?

Beyond action

Have you revisited the experiences?

• Have you reviewed your actions from earlier reflections for this activity?
• Identify specific actions you previously noted were needed to improve your practices, such as mastering a specific bioinformatic tool for splice site prediction or refining your application of ACMG/AMP guidelines—and determine if you have completed these.
• Are you now ready to demonstrate this new learning in practice for more complex cases, such as those involving rare indels or frameshifts?
• Has discussing a case with peers or colleagues in a variant classification meeting changed your view on how to assign clinical significance?

How have these experiences impacted upon current practice?

• Consider how the accumulated learning from interpreting these various sequence variants will support you in preparing for observed ‘in-person’ assessments for this module, such as a Case-based Discussion (CBD) on rare disease or a Direct Observation of Practical Skills (DOPS) titled ‘Classify a variant’.
• How has your practice developed and evolved over time? For example, can you see a clear improvement in your ability to synthesise evidence for missense variants compared to when you first started this activity?
• Are you more confident in recognising when a case is beyond your scope of practice, such as a variant in a gene with very limited clinical data, and knowing exactly when to escalate for senior review?
• How has this foundational experience in rare disease interpretation influenced your approach to other areas of genomics, such as understanding the implications of germline findings in a cancer context?

Relevant learning outcomes

#	Outcome
# 3	Outcome Interpret genomic variants to investigate the clinical significance using appropriate nomenclature.