Solid Cancers 1 —
Training activity: 6

Details

Perform variant interpretations for:

• Colorectal
• Lung
• Melanoma

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 performing variant interpretations for colorectal and lung cancer and melanoma. This involves evaluating the clinical significance of variants identified using a range of bioinformatics tools following best practice guidelines.
• Discuss with your training officer to gain clarity of what is expected of you in relation to the application of current nomenclature and the correlation of variants with appropriate therapeutics and disease management.

What is your prior experience of this activity?

• Think about what you already know about variant interpretation, specifically somatic and germline associations in solid cancers.
• Consider possible challenges you might face during the activity, such as interpreting variants of uncertain significance, distinguishing between somatic and germline variants, or integrating conflicting evidence regarding pathogenicity, and think about how you might handle them.
• Recognise the scope of your own practice for this activity i.e. know when you will need to seek advice or help, and from whom. You will need to seek advice from your Training Officer when required, for example when interpreting a highly complex or novel variant or when findings suggest an unexpected germline association.
• Acknowledge how you feel about performing the variant interpretations identified.

What do you anticipate you will learn from the experience?

• Consider the specific skills you want to develop, such as applying best practice guidelines for variant classification and integrating genomic findings with therapeutic strategies.
• Identify the specific insights you hope to gain into the clinical significance of driver and passenger mutations in colorectal and lung cancer and melanoma, or applying current nomenclature and genomic databases effectively.

What additional considerations do you need to make?

• Consult actions identified following previous experiences of data interpretation or variant classification exercises.
• Identify important information you need to consider before embarking on the activity, such as associated genomic aberrations and their role within diagnosis and disease management, the appropriate therapeutics to guide patient disease management, and relevant genomic databases.

In action

Is anything unexpected occurring?

• Are you noticing anything surprising or different from what you anticipate whilst classifying and determining the clinical significance of genetic variants?
• Are you encountering situations such as:
  • Conflicting information from different databases or literature sources regarding pathogenicity or clinical actionability?
  • Variants with limited or conflicting evidence regarding clinical significance (e.g., a variant of uncertain significance)?
  • Difficulty correlating genomic findings with the patient’s clinical context (e.g., the genomic result suggests resistance to a therapy the patient is currently receiving)?
  • Encountering complex or novel genomic alterations that challenge standard nomenclature?

How are you reacting to the unexpected development?

• How is this impacting your actions? For example, are you responding to the situation appropriately? Are you applying specific classification guidelines (e.g., national guidance) or performing additional database searches? Are you adapting or changing your standard variant interpretation workflow to account for the conflicting evidence?
• Consider the steps you are taking in the moment, such as immediately initiating a consultation with a senior colleague to discuss the ethical implications of conflicting therapeutic guidance.
• How are you feeling in that moment? For instance, are you finding it difficult to apply the current nomenclature to a novel finding? Is it affecting your confidence in accurately evaluating clinical significance?

What is the conclusion or outcome?

• Identify how you are working within your scope of practice. For example, are you successfully applying classification guidelines to resolve the conflicting data? Or are you needing support because the clinical correlation requires specialist input beyond the scope of molecular interpretation (e.g., germline counselling considerations)?
• What are you learning as a result of the unexpected development? For example, are you mastering a more comprehensive search strategy for identifying relevant clinical trials or therapeutic guidelines associated with complex variants of uncertain significance?

On action

What happened?

• Begin by summarising the key steps you took when performing variant interpretations for the colorectal and lungh and melanoma cases.
• Consider specific events, actions, or interactions which felt important, such as how you utilised genomic databases and best practice guidelines to evaluate the clinical significance of variants, or how you correlated somatic variants with potential treatment implications.
• Include any ‘reflect-in-action’ moments where you had to adapt to the situation as it unfolded, for instance, immediately expanding your literature search when a suspected pathogenic variant was listed as a variant of uncertain significance in a key database, complicating the final classification.
• How did you feel during this experience, e.g., did you feel acutely aware of the potential clinical impact of the variant or challenged by integrating conflicting evidence?

How has this experience contributed to your developing practice?

• Identify what learning you can take from this experience regarding the ability to evaluate the clinical significance of variants identified. What strengths did you demonstrate, e.g., systematic approach to reviewing multiple lines of evidence (databases, literature, clinical history) for pathogenicity?
• What skills and/or knowledge gaps were evident, e.g., uncertainty regarding the application of specific nomenclature rules for novel germline findings in colorectal cancer?
• Compare this experience against previous engagement with similar activities – were any previously identified actions for development achieved? Has your practice improved in evaluating the clinical significance of variants using bioinformatics tools?
• Identify any challenges you experienced, such as needing to seek advice or clarification on scope of practice regarding the interpretation of a variant with conflicting literature classifications, and how you reacted to this.

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 learnt, including from any feedback you have received, with regards to variant interpretations.
• What will you do differently next time you encounter a variant of uncertain significance in a melanoma case, for instance, by proactively reviewing all clinical trial evidence related to similar protein changes?
• Do you need to practise any aspect of the activity further, such as reviewing classification guidelines for complex somatic variants or key learning outcomes related to evaluating the clinical significance of variants?

Beyond action

Have you revisited the experiences?

• How have your subsequent experiences of performing variant interpretations for colorectal,lung and melanoma since completing this specific training activity led you to revisit your initial approach or decisions during that activity? For example, how a subsequent case requiring differentiation between somatic and germline associations forced you to re-evaluate the depth of your database review and classification protocol you applied during your first attempt at this training activity?
• Considering what you understand about evaluating the clinical significance of variants using a range of bioinformatics tools and best practice guidelines now, were the actions or considerations you identified after your initial reflection on this training activity sufficient? How have you since implemented or adapted improvements in your interpretation workflow based on further learning and experiences? For example, how you proactively streamlined your approach to using relevant genomic databases and academic literature to assess pathogenicity.
• Has discussing challenging or equivocal variant findings or the integration of genomic findings with therapeutic strategies with colleagues, peers, or supervisors changed how you now view your initial experience in this training activity? For example, how professional storytelling with a senior colleague about a case where classification was ambiguous, refined your understanding of the critical nature of documenting the evidence for variant significance and appropriate nomenclature?

How have these experiences impacted upon current practice?

• How has the learning from this initial training activity, in combination with subsequent experiences, contributed to your overall confidence and competence in performing variant interpretations for solid tumours, particularly in preparing for assessments like Direct Observations of Practical Skills (DOPS)? For example, how your accumulated ability in evaluating clinical significance now enables you to confidently interpret a somatic variant and discuss its relevance for diagnosis during a DOPS assessment?
• How has reflecting back on this specific training activity, combined with everything you’ve learned since, shaped your current approach to variant classification? How does this evolved understanding help you identify when something is beyond your scope of practice or requires escalation? For example, how your evolved approach means you now routinely seek advice immediately when interpreting a highly complex or novel variant of uncertain significance that requires specialist pathological input?
• Looking holistically at your training journey, how has this initial experience, revisited with your current perspective, contributed to your development in meeting the learning outcomes related to evaluating the clinical significance of variants identified?

Relevant learning outcomes

#	Outcome
# 3	Outcome Analyse, interpret and prepare interpretive reports of clinically relevant findings for patients with colorectal and lung cancer, and melanoma.
# 4	Outcome Evaluate the clinical significance of variants identified for colorectal and lung cancer, and melanoma using a range of bioinformatics tools following best practice guidelines.
# 5	Outcome Interpret the bioinformatic and NGS quality metrics in relation to assay performance and EQA.