MSH6 encodes a protein playing a key role in the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that occur during DNA replication and homologous recombination. MSH6 heterodimerizes with MSH2 to form a mismatch recognition complex functioning as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. MSH6 has been linked to Lynch Syndrome (autosomal dominant) and mismatch repair cancer syndrome (autosomal recessive), which were curated separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. This curation focuses on disputing the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control data.
Summary of Case-Control Data: 4 points
This gene-disease relationship has been studied in at least 5 case-control or cohort studies at the single or aggregate variant level.
There is evidence supporting the gene-disease relationship. BCAC, a large case-control study published in 2021 (PMID: 33471991), showed a significant association with moderate odds ratio (=1.96) of aggregated pathogenic MSH6 variants with breast cancer (3 point). Another case-control study reported by Lu et al. (PMID: 30128536) also demonstrated a significant association (Odds Ratio=2.59). However, the case population Lu et al. study includes breast cancer and/or ovarian cancer; therefore, the strength of this evidence is limited (1 point).
Evidence did not support the gene-disease relationship also reported. In 2021, a large case-control study [CARRIERS (PMID: 33471974) with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in MSH6 and breast cancer. Likewise, another two large case-control studies published in 2017 screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in MSH6 with breast cancer (PMID: 28418444, 35172496).
Overall Summary:
In summary, given that case-control studies show either a modest effect of increased risk, or no increased risk for colorectal cancer in monoallelic MSH6 variant carriers, the Hereditary Cancer GCEP has disputed this gene-disease association. More evidence is needed to either support or entirely refute the role MSH6 plays in autosomal dominant breast cancer. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 7/26/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).
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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