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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.