BRCA1-, BRCA2-, and PALB2-related Fanconi anemia: Scope to expand disease phenotypic features and predict breast cancer risk in heterozygotes

Johnatty, SE; Tudini, E; Parsons, MT; Michailidou, K; Zanti, M; Canson, DM; Davidson, AL; Berger, T; Rosti, RO; Kratz, CP; Kalb, R; McReynolds, LJ; Giri, N; Richardson, ME; Pesaran, T; Surrall&#233;s, J; Pujol, R; Vundinti, BR; George, M; Maxwell, KN; Nathanson, K; Domchek, S; Fiesco-Roa, M&#211;; Frias, S; Garc&#237;a-de-Teresa, B; Jongmans, M; Lalani, S; Maiburg, M; Prescott, K; Robinson, R; Rajagopalan, S; Blok, LS; Temple, SEL; Tucker, K; Auerbach, AD; Cancio, MI; Kennedy, JA; MacMillan, ML; Tryon, R; Wagner, JE; Walsh, M; Boddicker, NJ; Hu, C; Weitzel, JN; Dingemans, AJM; Hadler, J; Rotenberg, N; Ramadane-Morchadi, L; de la Hoya, M; James, P; van Overeem Hansen, T; Vreeswijk, MPG; Walker, LC; Sharan, SK; Easton, DF; Couch, F; Smogorzewska, A; Nelson, A; Ngeow, J; Tischkowitz, M; Gomez-Garcia, E; CARRIERS Consortium; Breast Cancer Association Consortium; ENIGMA Consortium; Spurdle, AB

Author(s): Johnatty, SE; Tudini, E; Parsons, MT; Michailidou, K; Zanti, M; Canson, DM; Davidson, AL; Berger, T; Rosti, RO; Kratz, CP; Kalb, R; McReynolds, LJ; Giri, N; Richardson, ME; Pesaran, T; Surrallés, J; Pujol, R; Vundinti, BR; George, M; Maxwell, KN; Nathanson, K; Domchek, S; Fiesco-Roa, MÓ; Frias, S; García-de-Teresa, B; Jongmans, M; Lalani, S; Maiburg, M; Prescott, K; Robinson, R; Rajagopalan, S; Blok, LS; Temple, SEL; Tucker, K; Auerbach, AD; Cancio, MI; Kennedy, JA; MacMillan, ML; Tryon, R; Wagner, JE; Walsh, M; Boddicker, NJ; Hu, C; Weitzel, JN; Dingemans, AJM; Hadler, J; Rotenberg, N; Ramadane-Morchadi, L; de la Hoya, M; James, P; van Overeem Hansen, T; Vreeswijk, MPG; Walker, LC; Sharan, SK; Easton, DF; Couch, F; Smogorzewska, A; Nelson, A; Ngeow, J; Tischkowitz, M; Gomez-Garcia, E; CARRIERS Consortium; Breast Cancer Association Consortium; ENIGMA Consortium; Spurdle, AB;
Details: Publication Year 2025-12-04,Volume 112,Issue #12,Page 2902-2921
Journal Title: American Journal of Human Genetics
Publication Type: Research article
Abstract: The recessive Fanconi anemia (FA) phenotype is used to classify BRCA1 (FANCS), BRCA2 (FANCD1), and PALB2 (FANCN) variants with respect to dominant hereditary breast-ovarian cancer syndrome. We assessed its utility by examining the phenotypic spectrum observed in individuals with bi-allelic BRCA1, BRCA2, or PALB2 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 sources (total n = 172, 43 previously unpublished). Distinct FA-related variants (15 BRCA1, 123 BRCA2, and 22 PALB2) were annotated for predicted molecular impact, location, observed splicing or functional impact, and potential in-frame splicing rescue and used to assign different permutations of allele severity scores, which were assessed for correlation with FA presentation features. The association of BRCA1 and BRCA2 allele severity score with the magnitude of breast cancer risk in heterozygotes was evaluated using case-control analysis. Clinical features extended beyond the HPO list, including 84 terms related by hierarchy and 94 additional terms. The BRCA2 genotype severity score was associated with age at cancer diagnosis in individuals with FA (p = 1.8 × 10(-8)). A similar permutation approach revealed significant differences in the magnitude of breast cancer risk according to the BRCA1 and BRCA2 allele severity score in heterozygotes. Our findings indicate the potential to redefine FA ORPHA:84 HPO terms and to use an allele severity scoring approach to predict cancer risk in individuals with bi-allelic or heterozygous BRCA1 or BRCA2 variants.
Publisher: Cell Press
Keywords: Humans; *Fanconi Anemia Complementation Group N Protein/genetics; Female; *Fanconi Anemia/genetics/pathology/complications; *BRCA2 Protein/genetics; Heterozygote; *BRCA1 Protein/genetics; Phenotype; *Breast Neoplasms/genetics/pathology; Genetic Predisposition to Disease; Alleles; Case-Control Studies; Hereditary Breast and Ovarian Cancer Syndrome/genetics; Adult; Acmg; Brca1; Brca2; Fanconi anemia; Human Phenotype Ontology; Palb2; breast cancer risk; genetic variant classification; pathogenicity
Department(s): Familial Cancer Centre
Publisher's Version: https://doi.org/10.1016/j.ajhg.2025.10.007
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-13 04:29:45

Last Modified: 2026-01-13 04:29:53