MRE11

Inheritance Pattern: AR

Disease ID:MONDO:0024557

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0024557

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0024557

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0024557

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0024557

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

MRE11 (also known as MRE11A) is part of the MRN (MRE11-RAD50-NBN) complex and is involved in repairing double strand breaks in DNA. Bi-allelic mutations in MRE11 are associated with the recessive Ataxia-telangiectasia-like disorder 1. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split MRE11 into two separate curations - one for the recessive Ataxia-telangiectasia-like disorder 1 and the second for hereditary breast cancer (refute the association with breast cancer) described here. Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of MRE11 in DNA damage repair. **Summary of Case-Control Data: 0 POINTS** This gene-disease relationship has been studied in at least 4 case-control studies at the aggregate variant level and 1 case-control cohort at the single 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 MRE11 and breast cancer. Likewise, another large case-control study published in 2017 (Couch et al. PMID: 28418444) screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in MRE11 with breast cancer. Two more case-control studies with smaller case and control sizes also showed no association of LOF or missense MRE11 variants with breast cancer (PMID: 29368209 and 29678143). **Summary of Experimental Data: 1 POINTS** While case control studies did not support the gene-disease association, there is experimental evidence showing the role of MRE11 in double-strand DNA break repair (0.5 point, PMID:9651580). Another study reported reduced MRE11 expression in breast cancer tissues (0.5 point, PMID:14511253). **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 MRE11 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 10/25/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0016248

Submitter: ClinGen

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).