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Variant classification

Source: vignettes/variant_classification.Rmd
variant_classification.Rmd

Oncogenicity

PCGR evaluates somatic aberrations (SNV/InDels) for oncogenic potential through an implementation of standard operating procedures proposed by ClinGen/CGC/VICC. Here, various properties of the variants and genes affected are assigned criteria-specific scores, both negative and positive, pending on whether the properties support an oncogenic or benign variant nature. Criteria-specific scores are in turn aggregated towards an overall oncogenicity score per variant.

Note that all properties/criteria provided in the SOP’s are not readily implemented in PCGR, specifically the ones requiring manual curation or expert review (i.e. experimental oncogenic variant evidence, requiring support from in vitro or in vivo functional studies (criteria OS2)). Also, the current source for existing oncogenicity classifications (ClinVar), which is needed for implementation of criteria OS1 and OM3, is considerably limited. Considering the current limitations, some oncogenic variants are likely to be missed and classified with uncertain significance (VUS) by PCGR. We highlight conventional ClinVar classifications (i.e. with respect to pathogenicity) alongside the current oncogenicity classifications, this may likely add value to the interpretation for uncertain cases. Furthermore, taking into the account the nature of the current implementation, we have adopted slightly different score thresholds for variant classifications to those proposed originally by Horak et al., 2022. We are working to further improve the oncogenicity classification in PCGR, and welcome feedback on this matter.

Note also that for somatic copy number aberrations, we showcase potential oncogenic events as proto-oncogenes subject to amplifications (where level of amplification is configurable by the user), as well as tumor suppressor genes subject to homozygous deletions.

The following criteria/codes are currently used for variant oncogenicity classification in PCGR (key resources/tools used for implementation indicated in parentheses):

  • ONCG_OVS1 - Null variant - predicted as LoF - in bona fide tumor suppressor gene (VEP;CGC;CancerMine)
  • ONCG_OS1 - Same amino acid change as previously established oncogenic variant - regardless of nucleotide change (ClinVar)
  • ONCG_OS3 - Located in a mutation hotspot with >= 50 samples with variant at AA position, >= 10 samples with same AA change (cancerhotspots.org)
  • ONCG_OM1 - Presumably critical site of functional domain (CIViC)
  • ONCG_OM2 - Protein length changes from in-frame dels/ins in known oncogene/tumor suppressor genes or stop-loss variants in a tumor suppressor gene (VEP;CGC;CancerMine)
  • ONCG_OM3 - Missense variant at an amino acid residue where a different missense variant determined to be oncogenic (using this standard) has been documented (ClinVar)
  • ONCG_OM4 - Located in a mutation hotspot with < 50 samples with variant at AA position, >= 10 samples with same AA change (cancerhotspots.org)
  • ONCG_OP1 - Multiple lines of computational evidence support of a damaging variant effect on the gene or gene product (dbNSFP)
  • ONCG_OP3 - Located in a mutation hotspot with < 10 samples with the same amino acid change (cancerhotspots.org)
  • ONCG_OP4 - Absent from controls (gnomAD) / very low MAF (any five major gnomAD subpopulations) (gnomAD)
  • ONCG_SBVS1 - Very high MAF (any five major gnomAD subpopulations) (gnomAD)
  • ONCG_SBS1 - High MAF (any five major gnomAD subpopulations) (gnomAD)
  • ONCG_SBP1 - Multiple lines of computational evidence support a benign variant effect on the gene or gene product (dbNSFP)
  • ONCG_SBP2 - Silent and intronic changes outside of the consensus splice site (VEP)

Actionability

PCGR prioritizes and evaluates variants according to clinical actionability. Currently, PCGR implements its tier classification framework along the proposed AMP/ASCO/CAP guidelines, as outlined in Li et al., 2017:

  • Tier I: Variants of strong clinical significance - constitutes aberrations linked to predictive, prognostic, or diagnostic biomarkers in the CIViC database and the Cancer Biomarkers Database that are
    • Found within the same tumor type/class as specified by the user, AND
    • Of strong clinical evidence (i.e. approved therapies, part of guidelines, validated or discovered in late clinical trials (CIViC evidence levels A/B))
  • Tier II: Variants of potential clinical significance - constitutes other aberrations linked to predictive, prognostic, or diagnostic biomarkers in the CIViC database and the Cancer Biomarkers Database that are either
    • Of strong clinical evidence in other tumor types/classes than the one specified by the user, OR
    • Of weak clinical evidence (early trials, case reports etc. (CIViC evidence levels C/D/E))) in the same tumor type/class as specified by the user
  • Tier III: Variants of uncertain clinical significance (SNVs/InDels only) -
    • Other coding variants, not observed at significant allele frequencies (gnomAD MAF < 0.001), found in oncogenes or tumor suppressor genes, yet not linked to any known predictive, prognostic, or diagnostic biomarkers in the CIViC database and the Cancer Biomarkers Database

In PCGR, we skip the classification of variants into the AMP/ASCO/CAP-specified Tier IV (benign/likely benign variants), but rather take a more cautious approach. Specifically, for SNVs/indels that do not fall into tier I, II, or III, we classify them into Tier V: Other coding variants, which includes protein-coding variants in non-cancer related genes, as well as Tier VI: Other non-coding variants, which includes synonymous variants, intronic variants, and other variants in non-coding regions.