Submission Details

PMS2 encodes a protein playing a key role in the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. PMS2 forms heterodimers with MLH1 to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is necessary for removal of the mismatched DNA. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. PMS2 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 and experimental data.

Summary of Case-Control Data: 0 point This gene-disease relationship has been studied in at least 3 case-control studies at the aggregate variant level. In 2021, a large case-control study [BCAC (PMID: 33471991) with more than 48 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in PMS2 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 PMS2 with breast cancer (PMID: 28418444, 35172496).

Summary of Experimental Data: 0 point Baker et al. (PMID: 7628019) demonstrated that mice with homozygous knockout of PMS2 did not develop tumors in breast or ovarian tissues. However, considering the short lifespan of mice, this evidence is not conclusive. Therefore, this evidence did not be scored or listed as a contradiction.

Overall Summary: In summary, large breast cancer case-control studies have shown the lack of significant association of PMS2 and breast cancer. However, considering that correct variant analysis of PMS2 is complex due to the presence of multiple pseudogenes and the occurrence of gene conversion, more evidence is needed to either support or entirely refute the role of PMS2 in hereditary breast cancer. The relationship between PMS2 and autosomal dominant hereditary breast cancer has currently been disputed. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 11/8//2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).