ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.2184+1G>T

gnomAD frequency: 0.00001  dbSNP: rs756363734
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222999 SCV000277794 likely pathogenic Hereditary cancer-predisposing syndrome 2023-12-18 criteria provided, single submitter clinical testing The c.2184+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 14 of the NBN gene. One study detected this alteration in 0/3030 pancreatic cancer cases and 2/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This alteration was detected in 1/1136 cases and 0/997 controls in a Nigeran breast cancer study (Zheng Y et al. J Clin Oncol, 2018 Oct;36:2820-2825), and was also detected in cohort of 1004 patients with osteosarcoma (Mirabello L et al. JAMA Oncol, 2020 May;6:724-734). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Counsyl RCV000411514 SCV000486752 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2016-08-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000411514 SCV000553125 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2024-01-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the NBN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28888541, 30130155). ClinVar contains an entry for this variant (Variation ID: 233424). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (Invitae). 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.
GeneDx RCV000478822 SCV000571724 likely pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing Canonical splice site variant reported to result in aberrant splicing (ClinVar SCV000553125.7, SCV001737449.2), disrupting the critical MRE11 interaction domain (Damiola et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast or ovarian cancer (Lilyquist et al., 2017; Zheng et al., 2018); This variant is associated with the following publications: (PMID: 29922827, 28888541, 30130155, 24894818)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000411514 SCV001737449 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2021-05-27 criteria provided, single submitter clinical testing The NBN c.2184+1G>T intronic change results from a a G to T substitution at the +1 position of intron 14 of the NBN gene. This variant is predicted to result in loss of the native splice donor site (PP3) and skipping of exon 14 has been confirmed by RNA studies (PVS1_Strong; internal data). This variant has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/8-90955480-C-A?dataset=gnomad_r2_1). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1_Strong, PM2_Supporting, PP3.
Revvity Omics, Revvity RCV000478822 SCV002017898 likely pathogenic not provided 2019-06-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000411514 SCV002045883 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411514 SCV004241475 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2023-12-14 criteria provided, single submitter clinical testing Variant summary: NBN c.2184+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 256404 control chromosomes (gnomAD and publication data). c.2184+1G>T has been reported in the literature in individuals affected with ovarian cancer, breast cancer or osteosarcoma (Lilyquist_2017, Zheng_2018, Mirabello_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35654374, 29922827, 28888541, 32191290, 30130155). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV003469077 SCV004199685 uncertain significance Aplastic anemia 2023-03-19 flagged submission 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.