Abstract
Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.
Highlights
Heterozygous pathogenic variants in the mismatch repair (MMR) genes predispose to Lynch syndrome (LS, OMIM #120435), known as hereditary nonpolyposis colorectal cancer (HNPCC), while homozygous or compound heterozygous pathogenic variants lead to constitutional
An artificial variant that is located in NLS2 p.(Lys301Asn), which later was reported in ClinVar as a variants of uncertain significance (VUS), showed increased cytoplasmic expression [64], suggesting that the NLS2 is important for nuclear localization of MSH6
MSH6 variants variants that that have have been been previpreviously examined by functional analysis, including activity, 6-TG
Summary
The integrity of the human genome is continuously challenged by exogenous and endogenous factors that cause DNA damage. If the MMR mechanism is compromised, e.g., due to pathogenic variants in the core genes, the mismatched nucleotides will persist as mutations in the round of replication, resulting in a hypermutator phenotype, including microsatellite instability, increasing the risk of developing cancer in specific tissues [1,2,3]. Heterozygous pathogenic variants in the MMR genes predispose to Lynch syndrome (LS, OMIM #120435), known as hereditary nonpolyposis colorectal cancer (HNPCC), while homozygous or compound heterozygous pathogenic variants lead to constitutional. Individuals with a pathogenic MMR variant have a high risk of developing early onset cancer, especially colorectal cancer (CRC) and endometrial cancer [6,7]. The cumulative risk at 70 years for endometrial cancer is 41%, which is comparable to MLH1 and MSH2 female carriers [18]
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