MLH3 encodes a gene for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. MLH3 was first reported in relation to autosomal dominant colorectal cancer, hereditary nonpolyposis, type 7 in 2001 (Wu et al., PMID: 11586295) and is also described as autosomal recessive colorectal cancer, hereditary nonpolyposis, type 7. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability with dominant and recessive disorders associated with MLH3. Therefore, these entities were not lumped and this curation solely focuses on autosomal dominant Colorectal cancer, hereditary nonpolyposis, type 7 (MONDO:0013725, OMIM:614385). Five heterozygous variants (four frameshifts and one missense) that have been reported in seven probands in 6 publications (PMIDs: 11586295, 12702580, 27401157, 28195393, 29212164 and 31043711) are included in this curation (3.2 points). No familial segregation analysis was scored since no family with four or more segregations were described, and reported co-segregation suggests a lack of association of disease with segregating MLH3 variants. Scores assigned in this curation were exclusively for colorectal cancers, as no probands were detected with other Lynch-associated tumors (endometrial, ovarian). In addition, 6 of 7 probands reported with loss of function MLH3 variants display tumors lacking MSI. Experimental evidence was curated for this gene-disease relationship (2.8 points), including protein interaction with other mismatch repair proteins (PMIDs: 10615123, 11292842 and 16322221). However, additional functional evidence shows the redundancy of MLH3 with PMS2 and suggests only a minor role for MLH3 in mismatch repair (PMIDs 10615123, 19156873). This gene-disease pair was originally evaluated by the Hereditary Cancer GCEP on 6/20/2022. It was reevaluated on 9/10/2024. As a result of this reevaluation, the classification changes from Moderate to Limited. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support a causal role of MLH3 and autosomal dominant colorectal cancer. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 09/27/2024 (SOP Version 10).
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).
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