ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2234+2T>G (rs142301194)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164379 SCV000215014 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-15 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508046 SCV000601686 likely pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000508046 SCV000618013 likely pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing This variant is denoted NBN c.2234+2T>G or IVS15+2T>G and consists of a T>G nucleotide substitution at the +2 position of intron 15 of the NBN gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant was identified in at least one individual referred for hereditary cancer testing (LaDuca 2017). Based on the currently available evidence, we consider NBN c.2234+2T>G to be a likely pathogenic variant.
Invitae RCV000636785 SCV000758226 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-10-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 15) of the NBN gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs142301194, ExAC 0.002%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 185026). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Aberrant splicing by this variant is expected to disrupt a portion of the C-terminal region of the NBN protein containing the ATM interaction domain (residues 734-754), which is important for activating ATM in DNA repair process (PMID: 21035407, 15964794, 15758953, 15048089). Experimental studies have shown that while cells from knockout mice lacking exon 15 recapitulating the possible splicing defect by this variant preserve checkpoint function, sensitivity to radiation, and chromosomal stability, the cells have a severely disrupted apoptotic function through abnormal ATM interaction (PMID: 17429352). This suggests that disruption of this region of the NBN protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000164379 SCV001341155 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.