Submission Details

MRE11 (previously known as MRE11A) constitutes a part of the MRN complex and encodes a nuclear protein involved in DNA double-strand break repair. Paull and Gellert in 1998 first reported the role of MRE11 in this pathway, while Heikkinen et al. in 2003 identified the first monoallelic germline variant in this gene in an ovarian cancer patient. MRE11 has been also linked to MRE11-related ataxia with oculomotor apraxia (autosomal recessive) and hereditary breast cancer (autosomal dominant), 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 refuting the association with familial ovarian cancer. Evidence curated in this gene-disease relationship includes case level and case-control data (0 Point), and experimental data (1 Point). Five studies (PMIDs: 14684699, 22006311, 29348823, 30441849, 31742824) identified MRE11 germline variants in ovarian cancer patients predominantly through multi-gene panel testing. However, the absence of co-segregation analysis in these studies raises uncertainties regarding whether the variants segregated with cancer. In two of these cases (Walsh et al., 2011 and Koczkowska et al., 2018), carriers were identified with concomitant BRCA1 or BRCA2 mutations, a known gene associated with ovarian cancer. Additionally, the pathogenicity of the MRE11 variants in these studies remains inconclusive due to the lack of supporting functional data. Importantly, multiple large case-control studies (PMIDs: 26720728, 28888541, 31406321, 33510186) presented no significant differences in MRE11 variant frequencies between cases and controls. Experimentally, Paull and Gellert (PMID: 9705271) demonstrated the specific enzymatic activities of MRE11 and its collaboration with RAD50 in repairing DNA double-strand breaks, emphasizing their roles in nonhomologous end-joining processes. Additionally, Zhong et al. (PMID: 10426999) found an interaction between BRCA1 and hRad50, forming a complex with hMre11 and p95/nibrin, suggesting BRCA1's cellular responses to DNA damage may be mediated by this complex. However, experimental studies establishing the specific association between MRE11 and familial ovarian cancer are lacking. In summary, given the lack of significant association in large ovarian cancer case-control studies to date, there is convincing evidence refuting the association between MRE11 and autosomal dominant familial ovarian 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 10/25/2017. This re-curation as refuted was approved by the ClinGen Hereditary Cancer GCEP on 12/15/2023 (SOP Version 10).