ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2140C>T (p.Arg714Ter) (rs730881864)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160804 SCV000211472 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing This variant is denoted NBN c.2140C>T at the cDNA level and p.Arg714Ter (R714X) 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 one individual with early onset breast cancer (Jian 2017) and is considered pathogenic.
Invitae RCV000204431 SCV000260258 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg714*) in the NBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730881864, ExAC 0.001%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 182737). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000215628 SCV000273524 pathogenic Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Fulgent Genetics,Fulgent Genetics RCV000515171 SCV000611218 likely pathogenic Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-18 criteria provided, single submitter clinical testing
Color RCV000215628 SCV000685755 pathogenic Hereditary cancer-predisposing syndrome 2015-02-23 criteria provided, single submitter clinical testing
Counsyl RCV000204431 SCV000796710 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-12-28 criteria provided, single submitter clinical testing
GeneKor MSA RCV000215628 SCV000821749 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000204431 SCV000917855 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-02-09 criteria provided, single submitter clinical testing Variant summary: NBN c.2140C>T (p.Arg714X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.4e-05 in 246018 control chromosomes in gnomAD. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (2.4e-05 vs 2.50E-03), allowing no conclusion about variant significance. The c.2140C>T variant has been reported in the literature in individuals affected with cancer (Susswein_2015, Jian_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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