ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.127C>T (p.Arg43Ter) (rs200287925)

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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 RCV000131193 SCV000186143 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-21 criteria provided, single submitter clinical testing The p.R43* variant (also known as c.127C>T), located in coding exon 2 of the NBN gene, results from a C to T substitution at nucleotide position 127. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of the NBN gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas MA et al. Science. 2015 May 8;348(6235):666-9; Lindeboom RGH et al. Nat. Genet. 2016 Oct;48(10):1112-8; Rhee JK et al. Sci. Rep. 2017 May 10;7(1):1653). Re-initiation on a downstream methionine would disrupt the forkhead-associated domain (FHA) which has been implicated in NBN function (Zhao S et al. Nucleic Acids Res. 2002 Nov;30:4815-22). However, the exact functional impact of this particular alteration is unknown at this time. This alteration has been reported in patients with breast cancer (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58; Thompson ER et al. J. Clin. Oncol. 2016 May;34:1455-9; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). It has also been identified in trans with a possible deleterious variant in an individual without features of Nijmegen breakage syndrome (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000409406 SCV000486041 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2016-04-05 criteria provided, single submitter clinical testing
GeneDx RCV000489509 SCV000577161 pathogenic not provided 2020-11-13 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24763289, 29625052, 25032700, 26976419, 26786923, 19523210, 24894818, 26787654, 29555771, 26689913, 32318955, 31980526)
Invitae RCV000409406 SCV000634213 pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg43*) in the NBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200287925, ExAC 0.03%). This variant has been reported in an individual undergoing hereditary cancer testing (PMID: 24763289), and an individual affected with triple negative breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 142203). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000131193 SCV000685707 pathogenic Hereditary cancer-predisposing syndrome 2020-10-22 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 2 of the NBN gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with breast cancer (PMID: 24894818, 26786923, 26976419). This variant has been identified in 8/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of NBN function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000409406 SCV000966851 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-04-18 criteria provided, single submitter clinical testing The p.Arg43X variant in NBN has been not been reported in individuals with Nijme gen breakage syndrome. However, it has reported in 1 individual with hereditary cancer and two individuals with breast cancer (LaDuca 2014, Tung 2016, Thompson 2016) and has been reported in ClinVar (Variation ID: 142203). The variant has b een identified in 4/22288 Finnish chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs200287925). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 43 which is predicted to lead to a tru ncated or absent protein. Loss of function of the NBS gene is an established dis ease mechanism in Nijmegen breakage syndrome. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg43X va riant is likely pathogenic for Nijmegen breakage syndrome. in an autosomal reces sive manner based upon predicted impact to the protein and absence from controls ,. ACMG/AMP Criteria applied: PVS1; PM2.

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