MLH3

Inheritance Pattern: AD

Disease ID:MONDO:0013725

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013725

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013725

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AR

Disease ID:MONDO:0015185

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0013725

Submitter: ClinGen

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).