ClinVar Miner

Submissions for variant NM_001024688.2(NBN):c.452_455del (p.Lys151fs) (rs587780100)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212735 SCV000149713 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing This deletion of four nucleotides in NBN is denoted c.698_701delAACA at the cDNA level and p.Lys233SerfsX5 (K233SfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GCCA[delAACA]Ggta, where the capital letters are exonic and lowercase are intronic. The deletion causes a frameshift, changing a Lysine to a Serine at codon 233, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously published as NBN or NBS1 698del4, has been reported in families with Nijmegen Breakage Syndrome as well as in women with breast and ovarian cancer (Varon 1998, Meyer 2004, Ramus 2015, Li 2016, Gass 2017), and is considered pathogenic.
Ambry Genetics RCV000115804 SCV000213967 pathogenic Hereditary cancer-predisposing syndrome 2018-04-12 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)
Genetic Services Laboratory, University of Chicago RCV000193543 SCV000248142 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-03-05 criteria provided, single submitter clinical testing
Invitae RCV000193543 SCV000261243 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys233Serfs*5) in the NBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780100, ExAC 0.01%). This variant has been observed in individuals affected with Nijmegen breakage syndrome (NBS), and breast/ovarian cancer (PMID: 9590180, 15474156, 26315354, 26534844). This variant is also known as 698del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 127878). 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 RCV000115804 SCV000685816 pathogenic Hereditary cancer-predisposing syndrome 2016-07-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212735 SCV000889556 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000193543 SCV000917863 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-08-03 criteria provided, single submitter clinical testing Variant summary: NBN c.698_701delAACA (p.Lys233SerfsX5) 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 2e-05 in 252006 control chromosomes (gnomAD). The variant, c.698_701delAACA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and Nijmegen Breakage Syndrome (Varon_1998, Gass_2017, Ramus_2015, Li_2015, Susswein_2016). 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. Six 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. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000193543 SCV000027554 pathogenic Microcephaly, normal intelligence and immunodeficiency 1998-05-01 no assertion criteria provided literature only
GeneReviews RCV000193543 SCV000494629 pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-02-02 no assertion criteria provided literature only

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