Analysis of , and related Fanconi anemia identifies scope to expand disease phenotypic features and predict breast cancer risk in heterozygotes.

Recessive Fanconi anemia (FA) phenotype is used in classification of , and variants with respect to dominant hereditary breast-ovarian cancer syndrome. We assessed its utility by examining the spectrum of phenotypes observed in individuals biallelic for , or pathogenic variants, and exploring the relationship between cancer presentation and allele severity score based on variant molecular features. A data collection instrument comprising 158 Human Phenotype Ontology (HPO) terms was used to document clinical features for individuals with FA from published and/or prospectively collected (total n=172, 43 previously unpublished) phenotypic data. Unique FA-related variants (15 , 123 , 22 ) were annotated for predicted molecular impact, location, observed splicing or functional impact, and potential in-frame splice rescue. Annotations were used to assign different permutations of allele severity scores, which were assessed for correlation with FA presentation features. The association of and allele severity score with magnitude of breast cancer risk in heterozygotes was evaluated using case-control analysis. Patient-detected features extended beyond the FA ORPHA:84 HPO list, including 84 terms related by hierarchy, and 94 novel terms. Genotype severity score was significantly associated with age at cancer diagnosis in FA individuals (p=1.8×10). A similar permutation approach revealed significant differences in magnitude of breast cancer risk according to and allele severity score in heterozygotes. Findings indicate potential to redefine the existing list of FA-related HPO terms, and to use an allele severity scoring approach to predict cancer risk in both FA patients and heterozygotes.