MLH3 was first reported in relation to MLH3 autosomal recessive intestinal polyposis syndrome in 2019 (Olkinuora et al., PMID: 30573798). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability with MLH3 -associated phenotypes. Therefore, the following disease entities have been split and curated separate disease entities: autosomal dominant Colorectal cancer, hereditary nonpolyposis, type 7 (MONDO:0013725, OMIM:614385), and autosomal recessive intestinal polyposis syndrome (http://purl.obolibrary.org/obo/MONDO_0015185). Two variants (nonsense and frameshift) that have been reported in five probands in two publications (PMIDs: 30573798, 31043711) are included in this curation of the recessive entity. Four probands from Finland reported in Olkinuora et al. all carry the same nonsense variant in a homozygous state, p.Ser1188Ter. At least one individual homozygous for the p.Ser1188Ter did not have any polyposis of gastrointestinal cancer described. One Swedish proband with polyps with the p.Ser1188Ter variant was also described in Olkinuora et al. Yang, et al. describes a proband homozygous for a different frameshift variant (p.Asp206ThrfsTer18) and no polyposis, but a diagnosis of rectal cancer at 44 years. The proposed mechanism of pathogenicity appears to be loss of function; however, no probands described in the literature display microsatellite instability or other evidence explaining the mechanism of tumorigenesis, again suggesting that MLH3 plays a minor role in mismatch repair. This gene-disease relationship is supported by one mouse model showing an accumulation of gastrointestinal tumors in homozygous MLH3 knockout mice (PMIDs: 18551179). Due to the frequency of the p.Ser1188Ter variant in the population studied (and presence of at least one homozygote in the gnomAD database), and the lack of replication of the initially-published data, there is limited evidence supporting the relationship between MLH3 and autosomal recessive intestinal polyposis syndrome. In summary, there is limited evidence to support this gene-disease relationship. This classification 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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