Invitae Nijmegen Breakage Syndrome Test


Test description

This test analyzes the NBN gene, which is associated with Nijmegen breakage syndrome (NBS). Individuals with pathogenic variants in both copies of the NBN gene can develop NBS, a rare condition whose features include short stature, microcephaly, intellectual disability, distinctive facial features, immunodeficiency, and increased risk for certain cancers. Individuals with a single pathogenic NBN variant are carriers of NBS and have an increased risk for adult-onset cancers including female breast or prostate cancer.

Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (1 gene)


Alternative tests to consider

NBN can also be ordered as part of a broader panel to test for different types of hereditary cancer conditions. Depending on the individual’s clinical and family history, one of these larger panels may be appropriate. Any of these larger panels can be ordered for no additional charge.

Nijmegen breakage syndrome (NBS)

Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive condition with features including short stature, microcephaly, intellectual disability, distinctive facial features, immunodeficiency, an increased risk of certain cancers, and premature ovarian failure in females.

Cognitive and motor skills are typically normal during the first year of life; these abilities decline thereafter and stabilize to static mild-to-moderate intellectual disability. Distinctive facial features include upslanting palpebral fissures, sloping forehead, prominent nose, large ears, and retrognathia. Most individuals with NBS have hyperpigmented or hypopigmented skin lesions. Up to half have clinodactyly, syndactyly, gastrointestinal anomalies, choanal atresia, cleft lip and palate, hydronephrosis, or hip dysplasia.

Immunodeficiency is characterized by low IgG, IgA, and T cells, which results in chronic and recurrent pulmonary infections. Approximately 50% of individuals with NBS develop non-Hodgkin lymphoma before age 15. Other associated cancers include central nervous system medulloblastoma, glioma, and rhabdomyosarcoma. Affected individuals have 50 times the general population’s risk of developing cancer.

Individuals with a single pathogenic NBN variant are carriers of NBS and have an increased risk of adult-onset cancers including female breast or prostate cancer.

Individuals with NBS have 50 times the general population risk of developing cancer. Up to 50% develop non-Hodgkin’s lymphoma by age 15. Most malignancies are lymphomas (45% of lymphomas are B-cell; 55% are T-cell). Other associated cancers include medulloblastomas, gliomas, and rhabdomyosarcomas.

Heterozygous carriers of a pathogenic NBN variant have up to a 30% risk of female breast cancer and increased risk of prostate cancer.

The NBN gene is the only gene known to be associated with Nijmegen breakage syndrome. Pathogenic variants are identified in almost 100% of affected individuals.

NBS is inherited in an autosomal recessive pattern. Individuals who inherit a single pathogenic NBN variant are at increased risk of female breast or possibly prostate cancer.

NBS is estimated to occur in 1 in 100,000 individuals.

NBN gene analysis may be considered in individuals with the following features:

  • microcephaly
  • growth deficiency
  • characteristic facial features (sloping forehead, retrognathia, prominent nose and nasal bridge, upslanting palpebral fissures, large ears)
  • recurrent infections
  • malignancies (B-cell and T-cell lymphoma)
  • decline in intellectual ability

Genetic testing for NBN may also provide informative results for patients with a personal or family history indicative of hereditary breast cancer whose initial testing of other high-risk genes has been negative or inconclusive.

Including genetic testing for NBN as part of a hereditary cancer panel can also increase the clinical sensitivity of the test for patients with a personal or family history of NBN-related cancers.

  1. Cybulski, C, et al. An inherited NBN mutation is associated with poor prognosis prostate cancer. Br. J. Cancer. 2013; 108(2):461-8. doi: 10.1038/bjc.2012.486. PMID: 23149842
  2. Cybulski, C, et al. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 2004; 64(4):1215-9. doi: 10.1158/0008-5472.can-03-2502. PMID: 14973119
  3. Demuth, I, Digweed, M. The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome. Oncogene. 2007; 26(56):7792-8. doi: 10.1038/sj.onc.1210876. PMID: 18066092
  4. Nagy, R, et al. Highly penetrant hereditary cancer syndromes. Oncogene. 2004; 23(38):6445-70. doi: 10.1038/sj.onc.1207714. PMID: 15322516
  5. National Library of Medicine, Genetics Home Reference: Nijmegen breakage syndrome. Accessed July 2015.
  6. Resnick, IB, et al. 657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls. Am. J. Med. Genet. A. 2003; 120A(2):174-9. doi: 10.1002/ajmg.a.20188. PMID: 12833396
  7. Seemanová, E. An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, immunodeficiency and chromosomal instability. Mutat. Res. 1990; 238(3):321-4. doi: 10.1016/0165-1110(90)90024-6. PMID: 2342514
  8. Steffen, J, et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int. J. Cancer. 2006; 119(2):472-5. doi: 10.1002/ijc.21853. PMID: 16770759
  9. UpToDate Online, Nijmegen breakage syndrome. Accessed July 2015.
  10. Varon, R, et al. Nijmegen Breakage Syndrome. 1999 May 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301355
  11. Zhang, B, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011; 12(5):477-88. doi: 10.1016/S1470-2045(11)70076-6. PMID: 21514219
  12. di, Masi, A, Antoccia, A. NBS1 Heterozygosity and Cancer Risk. Curr. Genomics. 2008; 9(4):275-81. doi: 10.2174/138920208784533610. PMID: 19452044

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
NBN NM_002485.4