ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.2238C>A (p.Tyr746Ter)

dbSNP: rs751570713
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Total submissions: 6
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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 2023-03-16 criteria provided, single submitter clinical testing The p.Y746* variant (also known as c.2238C>A), located in coding exon 16 of the NBN gene, results from a C to A substitution at nucleotide position 2238. This changes the amino acid from a tyrosine to a stop codon within coding exon 16. One study detected this mutation in 0/3030 pancreatic cancer cases and 1/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This stop codon occurs at the 3' terminus of NBN, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 9 amino acids of the protein. However, the truncation occurs in an ATM binding domain, and upstream of a nuclear localization signal. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000698449 SCV000827114 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2022-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr746*) in the NBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the NBN protein. This variant is present in population databases (rs751570713, gnomAD 0.0009%). 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: 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.
Genome-Nilou Lab RCV000698449 SCV002045879 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf RCV000698449 SCV004177252 uncertain significance Microcephaly, normal intelligence and immunodeficiency criteria provided, single submitter not provided
Baylor Genetics RCV004569120 SCV005056139 likely pathogenic Aplastic anemia 2024-02-23 criteria provided, single submitter clinical testing

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