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 pathogenic Hereditary cancer-predisposing syndrome 2018-12-05 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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 2018-05-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted NBN c.127C>T at the cDNA level and p.Arg43Ter (R43X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least three breast cancer patients (Damiola 2014, Thompson 2016, Tung 2016) and is considered pathogenic.
Invitae RCV000409406 SCV000634213 pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-12-23 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 RCV000131193 SCV000685707 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
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, http://gnomad.broadinstitute.org/; 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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