Associated disorders

The MRE11A 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 MRE11A gene has preliminary evidence supporting a correlation with autosomal dominant breast cancer in individuals who carry a single pathogenic variant.

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The detection and repair of DNA damage is an essential process to maintain proper genome function. The MRE11A gene encodes a protein required for normal double-strand DNA break detection and repair, and pathogenic variants in this gene are associated with the developmental disorder ataxia-telangiectasia-like disorder-1 (ATLD1). However, emerging evidence suggests that defects in DNA damage detection and repair underlie a number of ciliopathies, and that DNA repair proteins like MRE11A may be mutated in a subset of these disorders.

MRE11A heterozygote
MedGen UID: 764548

Clinical condition
There is preliminary evidence suggesting that pathogenic variants in MRE11A 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. MRE11A 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.

Gene information
The MRE11A gene is a component of the MRN complex, which is a protein complex consisting of the MRE11A, 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 MRE11A 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 MRE11A has a 50% risk of passing that variant on to offspring.

Additionally, individuals with a pathogenic variant in MRE11A are carriers of ataxia-telangiectasia-like disorder 1 (ATLD1). ATLD1 is an autosomal recessive condition that results when an individual inherits a pathogenic MRE11A 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 MRE11A 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 MRE11A 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 MRE11A 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 MRE11A 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

Assay and technical information

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.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
MRE11A NM_005591.3