Submission Details

MSH6 was first reported in relation to autosomal dominant Lynch Syndrome (LS, MONDO:0005835) in 1997 (Miyaki M. et al., PMID: 9354786). Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer (HNPCC), is a cancer predisposition syndrome; LS is caused by pathogenic germline variants (PGV) in DNA mismatch repair (MMR) genes, including MSH6, inherited in an autosomal dominant pattern. Biallelic MSH6 PGVs also cause a distinct mismatch repair deficiency cancer syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we separate these two curations due to different inheritance patterns and phenotype. This curation only focuses on the dominant LS condition. In this curation, we included 14 PGVs, including missense, deletions, nonsense, and duplications that have been reported in multiple patients and families (PMIDs: 9354786, 10521294, 36612224, 11709755, 26805314). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function (LOF). MSH6-Lynch Syndrome association is supported by experimental evidence at a biochemical and functional level (6 points). Drummond JT et al., 1995, (PMID: 7604264) describes the isolation of an MSH2–MSH6 heterodimer that restores DNA mismatch repair to tumor cells; in the same issue, Palombo F, et al., 1995, (PMID: 7604265) reported that the DNA mismatch recognition and binding in human cells has been thought to be mediated by the hMSH2 protein, they showed that the mismatch-binding factor consists of two distinct proteins, the 100-kilodalton hMSH2 and a 160-kilodalton polypeptide, GTBP (for G/T binding protein). Both proteins are required for mismatch-specific binding, a result consistent with the finding that tumor-derived cell lines devoid of either protein are also devoid of mismatch-binding activity. Sequence analysis identified GTBP as a new member of the MutS homolog family. Edelmann W, et al., (PMID: 9390556) also reported that extracts from the Msh6-/- cells were defective for the repair of single nucleotide mismatches. In addition, homozygous mice had a reduced lifespan and developed a spectrum of tumors. The mice showed tumors in the intestine (adenoma), the liver (hepatoma), and B- and T-cell lymphomas. In summary, MSH6 is definitively associated with autosomal dominant inheritance and Lynch Syndrome. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This gene-disease pair was initially evaluated by the Colon Cancer Expert Panel on 09/25/2017. It was reevaluated on 03/24/2023 (SOP Version 9). As a result of this reevaluation, the classification did not change.