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Somatic Cancer Variant Guidelines, Curation Models and Databases - A Decade of Development

15 Mar 2024
Venue: Metro Toronto Convention Center
Meeting Room: 714/16
Laboratory Genetics & Genomics
  • Accredited:
    • Accredited
  • Primary Categories:
    • Cancer
  • Secondary Categories:
    • Cancer
  • Level of Learner:
    • Intermediate
As whole exome and genome sequencing becomes increasingly utilized in the clinical management of sporadic cancer as well as hereditary cancer, the need for tools to interpret large numbers of genetic variants is apparent. A set of robust processes, data models and guidelines exist for germline variant classification. However, a parallel set of resources for interpretation of somatic variants are equally important. Inspired by systems for classifying germline variant pathogenicity, guidelines for the interpretation of clinically actionable somatic variants with therapeutic/predictive, prognostic or diagnostic value have been established by AMP/ASCO/CAP, ESMO and others. Standards for classifying oncogenicity of somatic variants have also been proposed for general adoption, including a schema by ClinGen, CGC and the VICC. Somatic variant knowledgebases have been established to house large numbers of somatic variant interpretations for private as well as public open use such as CIViC, OncoKB, and JAX-CKB. These knowledgebases also establish data models for the curation, housing, and distribution of somatic variants. The ClinVar database, with an established and widely used system for housing germline variation, is developing a model for incorporating somatic variation in collaboration with these ongoing somatic variant interpretation databases and classification efforts.  The ClinGen organization, which leverages expert working groups to tailor guidelines for specific genes and provide public curated variant interpretations, has similarly developed a parallel effort in the somatic space. Multiple ClinGen Somatic Cancer Variant Curation Expert Panels (SC-VCEPs) are being developed around different genes or disease groupings (FGFR, NTRK, FLT3, BCR::ABL-like ALL, etc), and undergoing a four step process for approval. CIViC has been selected as their primary knowledgebase for curation.  SC-VCEP somatic curation follows data models which incorporate the above-mentioned AMP/ASCO/CAP and ClinGen/CGC/VICC guidelines for clinical relevance and oncogenicity, which may be tailored for specific genes and disease contexts. Once approved, curated assertions in the CIViC knowledgebase from these SC-VCEPs are submitted to ClinVar with a three-star status. ClinGen Somatic currently has over 230 members who take part in 3 task forces and 5 SC-VCEPs, and have performed over 10,000 CIViC curations. The need for well-engineered systems for both germline and somatic variant interpretation in cancer, along with interoperable communication and open public availability of these large data sets is increasingly important. This session is intended to introduce ACMG members to a decade of work in the somatic cancer field from various efforts described above, including those developing guidelines (AMP/ASCO/CAP), knowledgebases (CIViC) and databases (ClinVar), and those leveraging large public curation efforts (ClinGen Somatic).

Learning Objectives

  1. Explain how addressing the somatic variant interpretation bottleneck problem accelerates precision oncology
  2. Describe how leveraging public curation and expert moderation can address the variant interpretation bottleneck
  3. Identify the distinction between clinical actionability and oncogenicity classifications
  4. Summarize somatic clinically actionable variant tiering and classification according to AMP/ASCO/CAP guidelines
  5. Describe how use of ClinGen/CGC/VICC oncogenicity classification enhances clinical variant interpretation and reporting
  6. Utilize CIViC evidence and assertions to assess the state of clinical knowledge for a somatic cancer variant
  7. Describe the need for expert-led gene specific modifications to general guidelines for somatic variant classification
  8. Discuss the recent updates to ClinVar to support the latest somatic variant guidelines
  9. Discuss the recent updates to ClinVar to support the latest somatic variant guidelines