Table I:

Overarching Learning Objectives of a Variant Interpretation Rotation

Learning Objective	Key Concepts	Skill building activities
Application of genomic technology concepts	(1) HGVS variant nomenclature standards	- Look up variants in reference databases, considering different naming conventions and/or legacy names when applicable - Use HGVS nomenclature to properly describe variants in written summaries and reports
	(2) Benefits and limitations of genomic tests and technologies	- Practice examples illustrating these points, and discuss with supervisor
	(3) Technical aspects of variant calling, filtering, and prioritization steps of genomic sequencing analyses	- Utilize a patient case to demonstrate how and when filtration criteria are applied
Critical use of genomics resources	(1) Critical use of databases and tools	- Look up variants in reference databases, including examples that demonstrate limitations of such databases and tools, discuss examples with supervisor
	(2) Critical evaluation of relevant medical literature	- Practice examples and discussion with supervisor - Read and assess biomedical literature relevant to patient variants
	(3) Identification and assessment of relevant evidence supporting/refuting variant pathogenicity	- Practice examples and discussion with supervisor - Identify and discuss key supporting/refuting evidence from both literature and database resources
Assessment of phenotypes	(1) Construction of a comprehensive disease narrative for a patient	- Review patient medical records and family history - Summarize patient narrative for supervisor
	(2) Identification of primary and secondary clinical features	- Practice examples and discussion with supervisor - Translate relevant clinical features to HPO terms using HPO browser
	(3) Identification of pertinent positive findings, and differentiation between pertinent negative findings and the absence of data	- Practice examples and discussion with supervisor - Translate relevant clinical features to HPO terms using HPO browser
Evaluation of gene-disease associations	(1) Weighting of a combination of different data types	- Read seminal readings on gene-level evidence evaluation (e.g. MacArthur et al., 2014; Strande et al., 2017)
	(2) Variants in the same gene can cause different diseases, and the same disease may present on a phenotypic spectrum	- Practice examples and discussion with supervisor
	(3) Evaluation of genes for their potential role in human disease, and assessment of the strength of available evidence	- Perform and write a literature review of gene-level evidence for a given gene, applying the conceptual framework, starting with selected training examples - Evaluate gene-disease associations and assign strength of evidence from patient cases
Review and classification of variants	(1) Variant interpretation uses a framework of explicit rules (e.g. ACMG/AMP guidelines)	- Read seminal papers on ACMG/AMP guidelines (Richards et al., 2015; Amendola et al., 2016; Biesecker & Harrison, 2018)
	(2) Variants must be interpreted within patient and disease context	- Practice variant assessment and assign classifications of example variants - Perform variant assessment and assign classification of patient variants - Summarize variant information in written and verbal formats
	(3) Different guidelines are applicable to different types of variants	- Practice assigning guidelines for example variants, and discuss with supervisor - Assess and classify an entire set of prioritized patient variants for at least one patient, under supervision and write up or present results
Standards and diversity in reporting criteria	(1) Reportability standards and deliverables vary according to test type, analysis setting, and finding type (primary, secondary, incidental)	- Read a variety of example reports
	(2) Communicate complex variant interpretation decisions, and underlying evidence, to genetics professionals	- Practice examples and discussion with supervisor - Write variant summaries for review by supervisor - Discuss variant summaries with rotation team members
	(3) Summarize complex genetics concepts to patients and study participants	- Report variants to genetics professionals and patients and/or study participants, under supervisor guidance