ATLD; HNGS1; MRE11A; MRE11B
The MRE11 gene is associated with autosomal recessive ataxia-telangiectasia-like disorder (ATLD) (MedGen UID: 348929). There is preliminary evidence suggesting a phenotypic overlap between ATLD and autosomal recessive Joubert syndrome (PMID: 22863007). Additionally, the MRE11 gene has preliminary evidence supporting a correlation with autosomal dominant breast cancer in individuals who carry a single pathogenic MRE11 variant (PMID: 14684699, 24894818).
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The MRE11 gene encodes for a nuclear protein that exhibits both exonuclease and endonuclease activity. MRE11 is a component of the MRN complex, which consists of the MRE11, RAD50 and NBN proteins. The MRN complex plays important roles in DNA double-strand break repair, meiotic recombination, cell cycle checkpoint control, and telomere maintenance. Loss of MRE11 function due to mutation is expected to alter MRN function, and therefore contribute to the onset of disease (PMID: 21035407).
MRE11 heterozygote (formerly known as MRE11A)
MedGen UID: 764548
There is preliminary evidence suggesting that pathogenic variants in MRE11 may be associated with a predisposition to breast and ovarian cancer (PMID: 24894818, 25452441, 19383352, 24894818, 14684699, 24549055). The risk for other cancers may be elevated as well, although this evidence is also emerging. MRE11 is therefore considered to be a “preliminary evidence” gene for autosomal dominant breast and ovarian cancer. preliminary evidence genes are selected upon extensive review of the literature and are expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, so clinicians may continue to order these preliminary evidence genes.
The MRE11 gene is a component of the MRN complex, which is a protein complex consisting of the MRE11, RAD50, and NBN genes. This complex plays a central role in double-strand break repair, DNA recombination, and maintenance of telomere integrity and meiosis (PMID: 19029686; UniProt consortium, UniProtKB – P49959 (MRE11_HUMAN); Accessed September 2015). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.
Individuals with a single pathogenic variant in MRE11 have a 50% chance of passing that variant on to their offspring. Once a variant is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). An individual with a variant in MRE11 has a 50% risk of passing that variant on to offspring.
Additionally, individuals with a pathogenic variant in MRE11 are carriers of ataxia-telangiectasia-like disorder 1 (ATLD1). ATLD1 is an autosomal recessive condition that results when an individual inherits a pathogenic MRE11 variant from each parent. This is a rare disorder that is characterized by progressive cerebellar ataxia, dysarthria, and abnormal eye movements in the absence of telangiectasia. While affected individuals display normal levels of total IgG, IgA, and IgM, there may be reduced levels of specific functional antibodies (PMID: 24733832, 15279810, 10612394, 18652530). For there to be a risk of ATLD1 in offspring, both parents would each have to have a single pathogenic variant in MRE11A; in such a case, the risk of having an affected child is 25%.
Because the evidence regarding MRE11 and breast and ovarian cancer risk is limited and preliminary, there are no guidelines or recommendations to suggest alteration to medical management based solely on the presence of a single pathogenic MRE11 variant. However, an individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.
Even though the data regarding individuals with a single pathogenic MRE11 are limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding MRE11 are likely to become available in the near future. Awareness of this variant encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Date reviewed: September 2015
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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