Submission Details

MBD4 was first reported in relation to autosomal MBD4-related recessive tumor predisposition syndrome in 2018 (Saunders et al., PMID: 30049810). This condition is a cancer predisposition syndrome with features such as acute myeloid leukemia, myelodysplastic syndrome, colorectal polyposis and carcinoma, and uveal melanoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive tumor predisposition syndrome (OMIM: 619975) and autosomal dominant uveal melanoma (OMIM: 606660). This curation only focuses on the recessive tumor predisposition syndrome assertion. Susceptibility to uveal melanoma has been curated separately. Six variants (missense, in-frame deletion, nonsense, and frameshift) that have been reported in at least 9 probands in 4 publications (PMIDs: 30049810, 35381620, 35460607; https://doi.org/10.1182/blood-2021-154221) are included in this curation. This gene encodes a protein that recognizes methylated CpG sites and has mismatch-specific glycosylase activity that functions in DNA repair. Deleterious variants lead to C>T mutations at CpG sites, which may be enriched in tumors. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence including a mouse model, functional alteration, and interaction evidence (PMIDs: 17285135, 27086921, 37957685). In the mouse model, homozygous null mice had more serious complications, reduced survival, and a higher tumor burden than wild-type controls. Also, functional alteration evidence showed that MBD4 is necessary for DNA methylation stability and G/T mismatch repair, and enzymatic activity is impaired in mutants. Furthermore, the gene was shown to interact with the MLH1 and PMS2 genes, both of which are definitive for autosomal recessive mismatch repair cancer syndrome and autosomal dominant Lynch Syndrome. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date 7/8/2024 (SOP Version 10).

MBD4 was first reported in relation to autosomal MBD4-related recessive tumor predisposition syndrome in 2018 (Saunders et al., PMID: 30049810). This condition is a cancer predisposition syndrome with features such as acute myeloid leukemia, myelodysplastic syndrome, colorectal polyposis and carcinoma, and uveal melanoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive tumor predisposition syndrome (OMIM: 619975) and autosomal dominant uveal melanoma (OMIM: 606660). This curation only focuses on the recessive tumor predisposition syndrome assertion. Susceptibility to uveal melanoma has been curated separately. Six variants (missense, in-frame deletion, nonsense, and frameshift) that have been reported in at least 9 probands in 4 publications (PMIDs: 30049810, 35381620, 35460607; https://doi.org/10.1182/blood-2021-154221) are included in this curation. This gene encodes a protein that recognizes methylated CpG sites and has mismatch-specific glycosylase activity that functions in DNA repair. Deleterious variants lead to C>T mutations at CpG sites, which may be enriched in tumors. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence including a mouse model, functional alteration, and interaction evidence (PMIDs: 17285135, 27086921, 37957685). In the mouse model, homozygous null mice had more serious complications, reduced survival, and a higher tumor burden than wild-type controls. Also, functional alteration evidence showed that MBD4 is necessary for DNA methylation stability and G/T mismatch repair, and enzymatic activity is impaired in mutants. Furthermore, the gene was shown to interact with the MLH1 and PMS2 genes, both of which are definitive for autosomal recessive mismatch repair cancer syndrome and autosomal dominant Lynch Syndrome. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date 7/9/2024 (SOP Version 11).