Submission Details

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).