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  • Test code: 01725
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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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. Varon, R, et al. Nijmegen Breakage Syndrome. 1999 May 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1176/ PMID: 20301355
  2. 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. PMID: 21514219
  3. 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. PMID: 16770759
  4. 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
  5. 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
  6. 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
  7. 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
  8. di, Masi, A, Antoccia, A. NBS1 Heterozygosity and Cancer Risk. Curr. Genomics. 2008; 9(4):275-81. doi: 10.2174/138920208784533610. PMID: 19452044
  9. Nagy, R, et al. Highly penetrant hereditary cancer syndromes. Oncogene. 2004; 23(38):6445-70. doi: 10.1038/sj.onc.1207714. PMID: 15322516
  10. 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
  11. UpToDate Online, Nijmegen breakage syndrome. http://www.uptodate.com/contents/nijmegen-breakage-syndrome Accessed July 2015.
  12. National Library of Medicine, Genetics Home Reference: Nijmegen breakage syndrome. http://ghr.nlm.nih.gov/condition/nijmegen-breakage-syndrome Accessed July 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 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
NBN NM_002485.4