Submission Details

FANCM was first reported in relation to an autosomal recessive FANCM Fanconi-like genomic instability disorder in 2018 (Bogliolo et al., PMID: 28837157 and Catucci et al., PMID: 28837162). Individuals with FANCM Fanconi-like genomic instability disorder show chromosome fragility, gonadal dysfunction, predisposition to develop certain tumors and increased chemosensitivity, however do not present with the hematological manifestations or congenital malformations associated with classical Fanconi anemia. Furthermore, individuals with chromosome fragility and gonadal dysfunction, without history of tumors, were first reported in 2017 (Fouquet et al., PMID: 29231814). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability for Fanconi-like syndrome (OMIM:227850), Premature ovarian failure 15 (OMIM:618096) and Spermatogenic failure 28 (OMIM:618086). Therefore, those disease entities have been lumped into one disease entity, FANCM Fanconi-like genomic instability disorder (OMIM:227850). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability for FANCM Fanconi-like genomic instability disorder (OMIM:227850), breast cancer predisposition (OMIM:114480) and Fanconi anemia (OMIM:PS227650). Therefore, those disease entities have been split into multiple disease entities. The split curations for breast cancer predisposition and Fanconi anemia have been curated separately. Six variants (nonsense, frameshift and splicing) that have been reported in 9 probands in 6 publications (PMID: 28837157, 28837162, 31942822, 34568721, 34793962, 37608704) are included in this curation. Although more evidence is available in the literature, the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence including a mouse model, rescue cell culture models and functional alteration (PMID:19561169, 19423727, 28837157). In the mouse model, homozygous null mice had gonadal abnormalities and a significant increase in tumor development compared to the wild-type controls. Patient-derived skin fibroblasts demonstrate chromosomal fragility, heightened sensitivity to interstrand crosslinks, and impaired monoubiquitination of FANCD2. These deficiencies may be effectively rescued through the restoration of the wild-type allele. Also, functional alteration evidence showed FANCM deficient lymphoblasts are hypersensitive to cytotoxic agents and no longer sensitive with the introduction of wildtype FANCM. In summary, there is definitive evidence supporting the relationship between FANCM and autosomal recessive FANCM Fanconi-like genomic instability disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on November 12, 2024 (SOP Version 11).