Ian King is a Clinical Molecular Geneticist at the Princess Margaret Cancer Centre in Toronto, Canada and an assistant professor at the University of Toronto. Ian is interested in development and implementation of tools for interpretation of somatic and hereditary sequence variants in clinical labs, and has a research interest in the genomics of melanoma and gynecological cancers. Ian is co-chair of the ClinGen Somatic Variant Curation Expert Panel for FGFR3 variants in urothelial cancer, and also serves as co-chair of the ClinGen Somatic Solid Tumor Taskforce.
Ian Kinga, Jason Salibab, Arpad Danosb, Ariana Gonzalezc, Bethany Baumannd, Christine Walkoe, Erin McMullinf, Gokce Torunerg, Jeanine Ruggerih, Sayed Ali Hosseinii, Kara Buij, Amber Pryzbylskik, Sameek Roychowdhuryl, Shashikant Kulkarnim, Obi L. Griffithb, Malachi Griffithb, Shamini Selvarajahn
aUniversity Health Network and University of Toronto, Toronto, ON, CA; bWashington University School of Medicine, St. Louis, MO, USA; cHeritas, Rosario, Santa Fe, Argentina; dPlanet Pharma/Genentech, Chicago, IL, USA; eMoffitt Cancer Center, Tampa, FL, USA; fBard College at Simon’s Rock, Great Barrington, MA, USA; gThe University of Texas MD Anderson Cancer Center, Houston, TX, USA; hUniversity of Michigan, Ann Arbor, MI, USA; iInvitae, South San Francisco, CA, USA; jCaris Life Sciences, Dallas, TX, USA; kMayo Clinic, Rochester, MN, USA; lOhio State University, Columbus, OH, USA; mBaylor College of Medicine, Houston, TX, USA; nUniversity Health Network, Toronto, ON, CA
Genomic aberrations disrupting fibroblast growth factor receptors (FGFR) signalling have been implicated in several human cancers and are an emerging focus of targeted therapies. While routine large-scale sequencing has resulted in the identification of numerous variants in the FGFR genes, these variants have never been uniformly and comprehensively classified for their clinical significance has been challenging due to their rarity. Thus, we formed the ClinGen FGFR Somatic Cancer Variant Curation Expert Panel (SC-VCEP) to standardize interpretation of FGFR gene variants, principally in FGFR3, but also FGFR1, FGFR2 and FGFR4 through adaptation of AMP/ASCO/CAP[PMID:27993330] and ClinGen/CGC/VICC [PMID: 35101336] guidelines.
Our SC-VCEP is composed of 17 multi-disciplinary members with expertise in FGFR mutation-driven neoplasms, and has received Step 1 approval from ClinGen. Our initial focus has been the assessment of FGFR3 variants in bladder cancers. Using publicly available variant curation databases, a set of 67 single nucleotide variants (SNVs) in FGFR3 was compiled and assessed using the recently published Oncogenicity Standards for Somatic Variants [PMID: 35101336]. From this process, we identified classification challenges including interpreting the intricacies and key metrics of functional assays, and identifying appropriate ensemble bioinformatics approaches for predicting the pathogenicity of FGFR variants. Our SC-VCEP is working to establish and validate specifications to address these gaps, which will ultimately support the generation of publicly available high-quality, clinically significant somatic cancer variant assertions in the CIViC knowledgebase and ClinVar.