Classification of variants detected by Oncopanel and Myeloid Panel testing is adapted from AMP/ASCO/CAP guidelines (Li (2017) PMID:27993330). Variant tiers reflect the known or predicted clinical significance of the variant in the relevant cancer type.
Criteria for classification includes the known or predicted functional consequence of the sequence change on normal gene function, as well as reported diagnostic, prognostic, or predictive clinical associations. Sources include professional practice guidelines, published literature, clinical trial criteria and results, population and cancer-specific variant databases, in silico software predictions, and internal laboratory data. Classifications may be updated over time in response to newly approved therapies, newly published predictive or prognostic associations, or changes in diagnostic criteria.
SOMATIC CLASSIFICATION TIERS:
TIER I – VARIANTS OF STRONG CLINICAL SIGNIFICANCE
Variants are predictive of response or resistance in a specific tumour type to therapies approved by Health Canada or US FDA. Alternatively, these variants are predictive, prognostic or diagnostic biomarkers in the specific tumour type, based on well-powered studies with consensus from experts in the field and inclusion in professional guidelines.
TIER II – VARIANTS OF POTENTIAL CLINICAL SIGNIFICANCE
Variants are predictive, prognostic or diagnostic biomarkers, based on convincing published evidence from smaller studies or case reports but without expert consensus.
TIER IIIA –VARIANTS OF UNCERTAIN CLINICAL SIGNIFICANCE
Variants are known or presumed to alter normal gene function, however no convincing published evidence of a predictive, prognostic or diagnostic association was found or evidence is sufficiently conflicting that a conclusion cannot be reached.
TIER IIIB – VARIANTS OF UNCERTAIN FUNCTION
Variants are not observed at a significant allele frequency in population, pan-cancer or tumour-specific variant databases and their effect on normal gene function cannot be confidently predicted. No convincing published evidence of a predictive, prognostic or diagnostic association was found or evidence is sufficiently conflicting that a conclusion cannot be reached.
TIER IV – BENIGN AND LIKELY BENIGN VARIANTS
Variants are known or presumed to not disrupt normal gene function, and/or are found at a significant allele frequency within the population. [Tier IV variants are not routinely reported.]
Germline variants are classified according to ACMG Guidelines (Richards (2015) PMID: 25741868) as one of:
- Likely Pathogenic
- Variant of Uncertain Significance (VUS)
- Likely Benign
The Likely Pathogenic and Likely Benign designations indicate an approximate 90% certainty in the classification. Benign and Likely Benign variants are not routinely reported.
POTENTIAL GERMLINE FINDINGS
Somatic sequencing panels detect variants that are of both somatic (acquired) and germline (inherited) origin. However, it is not routinely possible to distinguish between somatic and germline variants. Given that some of the genes targeted by these panels are associated with rare congenital and/or inherited cancer predisposition syndromes, certain variants may have hereditary significance if they are of germline origin.
Variants that represent these potential germline findings may be highlighted on the test report, along with a recommendation for referral to the Hereditary Cancer Program at BC Cancer for consideration of germline testing. See our Hereditary Cancer page for additional details on referrals.