NBN

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

Inheritance Pattern: Unknown

Disease ID:MONDO:0016419

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

NBN (previously known as NBS1) is part of the MRN (MRE11-RAD50-NBN) complex and is involved in repairing double strand breaks in DNA. Bi-allelic mutations in NBN are associated with the recessive Nijmegen Breakage Syndrome. Heterozygous mutations in NBN have been implicated in increased tumor burden and cancer risk. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split NBN into two separate curations - one for the recessive Nijmegen Breakage Syndrome (previously curated as Definitive) and this curation for breast cancer (refute the association with breast cancer). Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of NBN in DNA damage repair. **Summary of Case-Control Data: 0 POINTS** This gene-disease relationship has been studied in at least 2 case-control cohorts at the single variant level, 2 meta-analyses and 5 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in NBN and breast cancer. Likewise, other two large case-control studies published in 2017 screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in NBN with breast cancer (PMID: 28418444, 35172496). Damiola et al (PMID:24894818), when limited to truncating or splice variants only, also confirmed the lack of association to breast cancer in a set of ~1200 cases and controls. However, some small single variant studies and a meta-analysis find marginally significant associations to breast cancer. Aloraifi F, et al., 2015 (PMID: 2625098) that collected around 1200 breast cancer cases supported NBN and breast cancer. A small study by Buslov et al focused on bilateral breast cancer cases and found 2/173 cases carried c.657del5 while 0/344 controls harbored the variant. Zhang et al performed a meta-analysis of 10 breast cancer studies that queried the c.657del5 variant and found an OR of 2.66 (CI=1.82-3.9). Unfortunately, details of each study were not provided, and the cases and controls were not summarized; therefore, no point was assigned to these studies. **Summary of Experimental Data: 2 POINTS** There is experimental evidence of the role of NBN in double-strand DNA break repair. Gatei et al 2002 (PMID:10802669) showed NBN co-immunoprecipitates with ATM, a gene that has definitive classification for breast cancer (0.5 point). Gatei et al also showed NBN localization differences after radiation with 12 Gy of ionizing radiation (0.5 points). Dumon-Jones et al (PMID:14612522) found an increased burden of cancers seen in NBN heterozygous mice both with and without gamma radiation (1 point). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between NBN and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as limited by the Breast/Ovarian Cancer GCEP on 9/27/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0005212

Submitter: Genomics England PanelApp

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0012197

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: ClinGen

The NBN gene encodes nibrin protein, a member of the MRE11/RAD50/NBN (MRN) double-strand break repair complex that is involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. NBN variants have been associated with Nijmegen breakage syndrome (NBS), aplastic anemia, multiple cancers described below and breast cancer in individuals with heterozygous mutations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, this curation focuses solely on autosomal recessive NBS (MONDO: 0009623) due to the differences in inheritance pattern and phenotypic variability. The association with breast cancer for heterozygous mutation carriers was noted to be limited by ClinGen (PMIDs: 10802669, 11889050, 23765759, 25613900). NBN was first reported in relation to autosomal recessive NBS in 1998 (Varon et al., PMID: 9590180). NBS is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections due to immune deficiency, and an increased risk for cancer. Approximately 40% of NBS patients develop malignancies before age 20 years. Malignancies are primarily lymphomas (45% of lymphomas are of B cell origin and 55% are T cell lymphomas). In addition, solid tumors, including medulloblastomas, glioma, and rhabdomyosarcoma have been observed in NBS patients in their childhood (PMID: 20301355). Note that the curation for immune deficiency phenotypes in NBS was contributed by The Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) Gene Curation Expert Panel (please refer to the evidence summary addendum). 9 variants (nonsense and frameshift) that have been reported in more than 50 probands with NBS in 3 publications (PMIDs: 9590180, 12447395, 25677497) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. These variants are predicted to produce truncated protein (PMIDs: 9590180, 12447395) and immunoblotting demonstrates no nibrin protein expression in patient cells (PMIDs: 25677497). Thus, the mechanism of pathogenicity appears to be loss of function (LOF). Note that RAD50, another component of the MRE11-RAD50-NBN (MRN) complex, causes a Nijmegen breakage syndrome-like disorder. ATM and MRE11 are associated with an ataxia-telangiectasia(-like) disorder which shares a number of features in common with NBS. This gene-disease association is also supported by experimental evidence (11.5 points). Multiple NBN deficient mouse models have been established to show consistent phenotypes with NBS patients, including increased sensitivity to ionizing radiation, loss of the G2/M checkpoint, increased chromosome damage and susceptible to tumor development. (PMIDs: 11967151, 14612522, 15333589, 20921278). In summary, NBN is definitively associated with autosomal recessive NBS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. ---------- Evidence summary addendum: The Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) Gene Curation Expert Panel reviewed the association of immunodeficiency with Nijmegen Syndrome (NBS). Immune deficiency in NBS is characterized by variably decreased immunoglobulin levels, T cell lymphopenia and decreased T cell function associated with recurrent bacterial and viral infections (PMIDs:14632755, PMID:12390322). Immunodeficiency is found in patients with the common 657del5 variant and can also be found in other nonsense variants associated with NBS (PMID: 15451479; PMID:25677497). Some NBS patients can be identified through newborn screening analyzing T-cell excision circles (TRECs), and most NBS patients demonstrate low TRECs number throughout life (PMIDs: 28791007, 25677497). Functional evidence further supports the gene-disease relationship for NBN and immunodeficiency, including mouse models demonstrating NBN’s role in T cell receptor recombination (PMID: 20921278), rescue of the immune phenotype with successful BMT (PMID: 19684627) and expression studies (PMIDs: 25677497,15451479). The SCID-CID GCEP curated an additional two variants with further description of immunological findings. This addendum was approved by the SCID-CID Gene Curation Expert Panel on the meeting date March 17, 2022.

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009623

Submitter: Labcorp Genetics (formerly Invitae)