AT-V1; AT-V2; ATV; NBS; NBS1; P95
The NBN gene is associated with an increased risk for autosomal dominant breast cancer in individuals who carry a single pathogenic NBN variant (PMID: 21514219, 16770759). Additionally, the NBN gene is associated with autosomal recessive Nijmegen breakage syndrome (NBS) (MedGen UID: 140771).
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NBN is a tumor-suppressor gene that encodes nibrin, a protein that functions in cellular response to DNA damage and the maintenance of chromosomal integrity as part of the MRE11/RAD50/NBN double-strand break repair complex. Nibrin also has a role in regulating cell division and proliferation. Loss of nibrin function due to pathogenic variants causes defective DNA repair, leading to accumulation of DNA damage, thereby increasing the risk of tumor formation. A lack of functional nibrin also results in decreased immune cell proliferation.
Women with a single pathogenic NBN variant have up to a 30% risk for breast cancer (PMID: 16770759, 21514219, 19452044, 24113799). In men, there is an increased risk of prostate cancer, although a specific risk increase has not been established (PMID: 23149842, 14973119, 19452044). NBN may also be associated with increased risks for other cancer types, including ovarian (PMID: 22006311, 26315354), colorectal (PMID: 15185344), pancreatic (PMID: 27150568), hematologic malignancies (PMID: 12833396, 19452044, 24113799), and gastric cancer (PMID: 21171015, 19452044), however, the evidence is currently limited. While an individual with an NBN pathogenic variant will not necessarily develop cancer in his/her lifetime, the risk of cancer is increased when compared to that of the general population.
The NBN gene product functions in cellular response to DNA damage. As part of the MRE11/RAD50/NBN complex, it is involved in the maintenance of chromosomal integrity (UniProtKB – O60934 (NBN_HUMAN) http://www.uniprot.org/uniprot/O60934. Accessed January 2017). A pathogenic variant of this gene does not function normally, leading to an increased risk of developing certain types of cancer.
Hereditary predisposition to cancer due to pathogenic variants in the NBN gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for the 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).
Individuals with a pathogenic variant in NBN are also carriers of Nijmegen breakage syndrome (NBS). NBS is an autosomal recessive condition that results when an individual inherits a pathogenic NBN variant from each parent. It is a progressive multisystemic disorder that characterized by physical abnormalities, immunodeficiency, increased cancer risk, and cognitive impairment (PMID: 20301355). Physical abnormalities may include progressive microcephaly, early growth retardation leading to short stature, and distinctive facial features. Immunodeficiency often results in recurrent pulmonary infections (PMID: 20301355). B-cell lymphomas are the most common malignancy, although T-cell lymphomas, medulloblastomas, gliomas, and rhabdomyosarcomas may also occur (PMID: 20301355). The offspring can only develop NBS if both parents have a pathogenic variant in NBN; in this case, the risk of having an affected child is 25%.
The National Comprehensive Cancer Network® (NCCN®) has published screening and surveillance guidelines for women with a single pathogenic variant in NBN (NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017), which include the following suggestions:
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.
Knowing if an NBN 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 NBN 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 recommended screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian. V.2.2017. © National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed June 10, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.
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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