Mikk Tooming is a Junior Researcher at the University of Tartu and a Senior Research & Development Laboratory Specialist at Tartu University Hospital. His research focuses on the genetic etiology of hereditary breast and ovarian cancer, with particular emphasis on genotype-phenotype relationships and the prevalence of pathogenic cancer-associated variants in the Estonian population.
Combining expertise in cancer genetics, molecular diagnostics, and clinical laboratory genomics, his work aims to improve the identification and characterization of hereditary cancer risk factors. Through both research and diagnostic activities, he contributes to the advancement of precision medicine and the integration of genomic data into personalized cancer prevention, diagnosis, and patient care in Estonia.
Potential Founder BRCA2 Germline Genetic Variant in Estonia
Mikk Tooming1.2, Kanwal Batool3, Kadri Rekker2, Kadri Toome2, Piret Laidre2, Estonian Biobank Research Team3, Erik Abner3, Katrin Õunap1.2, Tiina Kahre1.2
1 Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia, 2 Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia; 3 Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
Background: Pathogenic variants (PV) in BRCA1 and BRCA2 are major contributors to hereditary breast and ovarian cancer (HBOC). While founder variants have been described in several populations, population-specific BRCA variants in Estonia remain largely unexplored.
Study question: Does the NM_000059.4(BRCA2):c.8572C>T p.(Gln2858*) pathogenic variant represent a founder variant in the Estonian population?
Methods: We analyzed a clinical cohort of 7,087 individuals referred for molecular testing at Tartu University Hospital between 2007 and 2023, including 2,856 breast cancer cases, 759 ovarian cancer cases, and 3,472 healthy family members. Genetic testing utilized APEX microarrays, Sanger sequencing, and next-generation sequencing panels. Population prevalence and geographic distribution were evaluated in the Estonian Biobank (EstBB; n=207,954) using genotyping array and imputed genetic data.
Main results: The BRCA2 c.8572C>T variant was the most frequent BRCA2 PV in the clinical cohorts, identified in 20 breast cancer (0.7%), 7 ovarian cancer patients (0.9%), and 48 healthy relatives (1.4%). In EstBB, 146 carriers were detected, corresponding to an estimated prevalence of approximately 1 in 1,424 individuals. The variant is rare in other populations and exhibited marked geographic clustering in southeastern Estonia. Population structure analyses demonstrated that carriers clustered within the local Estonian genetic background, supporting a shared ancestral origin.
Limitations: Haplotype analysis has not yet been performed to directly confirm a common ancestral chromosome carrying the variant.
Wider implications: These findings strongly support BRCA2 c.8572C>T as a likely Estonian founder PV originating from southeastern Estonia. Recognition of this variant could improve targeted genetic testing strategies, cancer risk assessment, genetic counseling, and cascade screening in Estonia.
Funding: PRG2040, PRG1291, TT17, PLTGIARENG24