ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2238C>A (p.Tyr746Ter) (rs751570713)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564630 SCV000662720 likely pathogenic Hereditary cancer-predisposing syndrome 2016-08-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting pathogenic classification,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000578737 SCV000680808 uncertain significance not provided 2017-04-10 criteria provided, single submitter clinical testing This variant is denoted NBN c.2238C>A at the cDNA level and p.Tyr746Ter (Y746X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA). This variant has not, to our knowledge, been reported in the literature. NBN Tyr746Ter results in the loss of 9 amino acids at the end of the protein, which might affect normal function. However, due to the location of the newly created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated decay and could therefore encode a truncated protein that retains some normal function. The deleted residues are located in the region of interaction with ATM (Damiola 2014). NBN Tyr746Ter was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available evidence, it is unclear whether NBN Tyr746Ter is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000564630 SCV000690703 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Invitae RCV000698449 SCV000827114 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-09-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NBN gene (p.Tyr746*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 9 amino acids of the NBN protein. This variant is present in population databases (rs751570713, 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: 480044). 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.

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