FANCM

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0054862

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

FANCM was first reported concerning autosomal dominant inheritance and breast cancer susceptibility in 2015 (Peterlongo P, et al., PMID: 26130695). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we lumped the recessive disorders premature ovarian failure 15 (MONDO:0054862), spermatogenic failure 28 (MONDO:0054732), and FA-like syndrome(MONDO:0009217) and split recessive disorder Fanconi Anemia (MONDO: 0019391) due to substantial differences in phenotype and inheritance pattern from breast cancer risk. The potential increased risk of breast cancer in individuals with heterozygous FANCM variants has been studied over the last decade, and although some studies show an increased risk (33471974, 33471991, 34584094, 36707629), others do not (38063144). One variant (FANCM: c.1972C>T) reported in breast cancer patients in one publication (PMID: 31700994) is included in this curation. More evidence is available in the literature (33471974, 33471991, 34584094, 36707629), reported associations between protein-truncating variants or missense variants in FANCM and breast cancer. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence from in vitro functional assays (PMID: ). The FANCM: c.1972C>T variant results in a truncated protein that lost the binding domains to the FA core, to Bloom´s complex and the FAAP24 protein. In summary, limited evidence supports the relationship between FANCM and autosomal dominant inheritance Breast cancer susceptibility. This relationship has been demonstrated in patients with monoallelic pathogenic variants in FANCM (PMIDs: 26130695, 31700994). The ClinGen Hereditary Cancer GCEP approved this classification on the meeting date of November 22, 2024 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0054732

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100578

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0018393

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0054732

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0054732

Submitter: Labcorp Genetics (formerly Invitae)