MSH2 gene encodes MSH2 protein, which heterodimerizes with MSH6 or MSH3 to form MSH2-MSH6 or MSH2-MSH3 complex (also named MutSα and MutSβ, respectively). Both MutSα and MutSβ are required 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. MSH2 has been linked to Lynch Syndrome (autosomal dominant) and mismatch repair cancer syndrome (autosomal recessive), which were curated separately. This curation focuses on refuting the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control data and experimental data.
Summary of Case-Control Data: 0 POINTS
This gene-disease relationship has been studied in at least 5 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in MSH2 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 MSH2 with breast cancer (PMID: 28418444, 35172496). In addition, Slavin et al 2017 (PMID:28649662) showed no significant association of pathogenic MSH2 variant with breast cancer although with large confidence intervals (OR:4.72, 95% CI:0.687-22.8).
Summary of Experimental Data: 1 POINTS
While case control studies did not support the gene-disease association, there is experimental evidence showing that MSH2 physically interacts with estrogen receptors (0.5 point, PMID:15886699). Another study reported negative staining in breast cancer tissues, while normal MSH2 expression was observed in adjacent normal tissues (0.5 point, PMID:30149959).
Overall Summary:
In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between MSH2 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 10/11/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (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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