Most Fanconi anemia heterozygotes are not at increased cancer risk: A genome-first DiscovEHR cohort population study.

Purpose: Fanconi anemia (FA) is a bone marrow failure and cancer predisposition syndrome caused primarily by biallelic pathogenic variants in 1 of 22 genes involved in DNA interstrand cross-link repair. An enduring question concerns cancer risk of those with a single pathogenic FA gene variant. To investigate all FA genes, this study utilized the DiscovEHR cohort of 170,503 individuals with exome sequencing and electronic health data.

Methods: 5822 subjects with a single pathogenic variant in an FA gene were identified. Two control groups were used in primary analysis deriving cancer risk signals. Secondary exploratory analysis was conducted using the UK Biobank and The Cancer Genome Atlas.

Results: Signals for elevated cancer risk were found in all 5 known cancer predisposition genes. Among the remaining 15 genes associated with autosomal recessive inheritance cancer risk signals were found for 4 cancers across 3 genes in the primary cohort but were not validated in secondary cohorts.

Conclusion: To our knowledge, this is the first and largest FA heterozygote study to use genomic ascertainment and validates well-established cancer predispositions in 5 genes, whereas finding insufficient evidence of predisposition in 15 others. Our findings inform clinical surveillance given how common pathogenic FA variants are in the population.