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 2020-07-30 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. 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.
Color Health, Inc RCV000564630 SCV000690703 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 16 of the NBN gene, creating a premature translation stop signal in the last coding exon and is predicted to truncate the last C-terminal 9 amino acids in the NBN protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. While an experimental study has shown the C-terminus of NBN can affect ATM-dependent DNA damage responses (PMID: 17507690), this effect could be attenuated (PMID: 20010693) therefore the precise impact of this change is inconclusive. This variant has been reported in an unaffected control in a pancreatic cancer case-control study (PMID: 29922827). This variant has been identified in 1/250384 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV000698449 SCV000827114 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-08-14 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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