ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.2206G>T (p.Glu736Ter)

dbSNP: rs756831345
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665016 SCV000789069 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2016-12-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000665016 SCV000942219 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2023-02-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu736*) in the NBN gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs756831345, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 550305). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. A deletion of 20 amino acids at the C-terminal of NBN protein has been reported to impair ATM binding (PMID: 15758953). The conserved ATM binding motif described in the literature is also deleted in this c.2206G>T variant (PMID: 15758953). Studies have shown that this premature translational stop signal results in skipping of exon 15 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the ATM interaction domain of the NBN protein (PMID: 24894818, 21035407), which is important for activating ATM in the double-strand break repair pathway (PMID: 15964794, 15048089). While functional studies have not been performed to directly test the effect of this variant on NBN protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001014726 SCV001175471 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-25 criteria provided, single submitter clinical testing The p.E736* variant (also known as c.2206G>T), located in coding exon 15 of the NBN gene, results from a G to T substitution at nucleotide position 2206. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theNBN gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 19 amino acids of the protein. The exact functional effect of this alteration is unknown; however, this alteration disrupts the C-terminus of the NBN protein which has been shown to be necessary for binding to the ATM protein (Falck J et al. Nature. 2005 Mar;434:605-11). This alteration was observed with an allele frequency of 0.028 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.089 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0010 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was also identified in a cohort of Chinese gastric adenocarcinoma patients (Ji K et al. Chin J Cancer Res. 2020 Aug;32:508-515). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV000665016 SCV002046033 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Natera, Inc. RCV000665016 SCV001454563 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-09-16 no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003163056 SCV002758168 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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.