NBSLD; RAD50-2; RAD502; hRad50
The RAD50 gene is associated with an increased risk for autosomal dominant breast cancer in individuals who carry a single pathogenic RAD50 variant (PMID: 14684699, 16474176, 24894818).
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The RAD50 gene encodes for a nuclear protein that exhibits ATP binding and regulatory activity. RAD50 is a component of the MRN complex, which consists of the MRE11A, 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 RAD50 function due to mutation is expected to alter MRN function, and therefore contribute to the onset of disease (PMID: 10346816, 21035407).
Women who are carriers of a single pathogenic RAD50 variant have an increased risk of breast cancer, though exact risk figures have yet to be determined (PMID: 24894818, 16474176, 14684699). There are also data associating the RAD50 gene with ovarian cancer, though these data are limited (PMID: 25622547). An elevated risk for other cancers has been considered, but available evidence is insufficient to make a determination at this time (PMID: 22006311, 14684699, 24549055). While an individual with a RAD50 pathogenic variant will not necessarily develop cancer in her lifetime, her risk for cancer is increased over that of the general population.
The RAD50 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; UniProtKB – Q92878 RAD50_HUMAN; Accessed July 2016. 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.
Hereditary predisposition to cancer due to pathogenic variants in the RAD50 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation 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 RAD50 has a 50% risk of passing that variant on to offspring.
There is preliminary evidence suggesting that the RAD50 gene is associated with Nijmegen breakage syndrome-like disorder (NBSLD). NBSLD is an autosomal recessive condition that results when an individual inherits a pathogenic variant from each parent. This condition is characterized by a clinical phenotype resembling Nijmegen breakage syndrome—including chromosomal instability, radiosensitivity, neurodevelopmental disease, and immunodeficiency—but with a milder clinical presentation (PMID: 19409520). For there to be a risk of NBSLD in offspring, both parents would each have to have a pathogenic variant in RAD50; in such a case, the risk of having an affected child is 25%.
At this time, there are no published guidelines or recommendations suggesting RAD50-specific medical management; however, due to the associated increased risk of breast cancer in women with a pathogenic RAD50 variant, enhanced or more frequent cancer screening may be warranted. 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 data regarding pathogenic RAD50 variants and the associated risk of breast cancer is 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 RAD50 are likely to become available in the near future. Awareness of this cancer predisposition 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.
Review date: July 2016
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|