Submission Details

FANCM was first reported in relation to autosomal recessive Fanconi anemia in 2005 (Ruhikanta Meetei et al., PMID:16116422). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability for Fanconi-like syndrome (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-like syndrome have been curated separately. Two variants (nonsense, deletion) that have been reported in one proband in one publication (PMID:16116422) are included in this curation and scored at 0 points. The mechanism of pathogenicity was reported to be loss of function. However, a later publication (PMID:19423727) has shown the proband also carried biallelic Fanconi anemia-causing variants in FANCA. This gene-disease relationship is also not supported by experimental evidence, including in a mouse model (PMID:19561169). In the mouse model, homozygous null mice had gonadal abnormalities and a significant increase in tumor development compared to the wild-type controls. However, the mice do not have congenital anomalies or hematopoietic abnormalities expected if a deficiency of FANCM caused Fanconi anemia. Similarly, humans with biallelic loss of function FANCM variants have not developed spontaneous bone marrow failure and do not have congenital anomalies (PMID: 28837157, 28837162, 31942822, 34568721, 34793962, 37608704). In summary, there is evidence refuting the relationship between FANCM and autosomal recessive Fanconi anemia. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date December 10, 2024 (SOP Version 11).