ClinVar Miner

Submissions for variant NM_001024688.2(NBN):c.411_415del (p.Lys137fs) (rs587776650)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212733 SCV000149712 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing The NBN c.657_661delACAAA deletion causes a frameshift, which changes a Lysine to an Asparagine at codon 219, and creates a premature stop codon at position 16 of the new reading frame. NBN 657del5 has been described as a pathogenic founder variant of Slavic and Eastern European origin and is the most common pathogenic variant in patients with the related autosomal recessive condition called Nijmegen Breakage syndrome (Varon 1998). An in vitro study conducted by Lins et al. (2009) found that there was some selective loss of the mutant allele associated with this deletion, but much less than would be expected for mRNA eliminated by nonsense-mediated decay (NMD). In addition, RT-PCR analysis revealed no significant difference in NMD rate between the mutant and wild-type mRNA, suggesting that NMD is not the mechanism by which this variant exerts its effect (Lins 2009). This variable mRNA expression and degradation may explain the range of cancer risks that have been observed in association with this pathogenic variant.
Ambry Genetics RCV000133576 SCV000183792 pathogenic Hereditary cancer-predisposing syndrome 2017-08-03 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)
Invitae RCV000007353 SCV000218835 pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-01-10 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 6 of the NBN mRNA (c.657_661delACAAA), causing a frameshift at codon 219. This creates a premature translational stop signal and would generally be expected to result in an absent or disrupted protein product. However, experimental studies have shown that this deletion introduces two in-frame start codons downstream of the frameshift, which can initiate protein translation and generate two truncated NBN proteins of similar length that maintain partial functionality (PMID: 11279524). This variant is present in population databases (rs587776650, ExAC 0.03%). This is the most common variant reported in individuals affected with Nijmegen breakage syndrome, and is considered to be a founder mutation in the Slavic population (PMID: 9590180). It is also known as 657del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 6940). Heterozygous carriers may have increased risk for several types of cancers including breast, lymphoma, prostate, melanoma, medulloblastoma and others (PMID: 15185344, 14973119, 18606567, 19908051, 24113799). In a large meta-analysis involving 15,184 cases and 54,081 controls from 21 studies, this variant was found to increase overall cancer risk in heterozygous carriers by close to three-fold (PMID: 24113799). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000007353 SCV000248141 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-03-04 criteria provided, single submitter clinical testing
Miami Human Genetics,University of Miami Miller School of Medicine RCV000007353 SCV000256868 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-11-16 criteria provided, single submitter research
University of Washington Department of Laboratory Medicine,University of Washington RCV000133576 SCV000266100 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000133576 SCV000292133 pathogenic Hereditary cancer-predisposing syndrome 2015-02-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415248 SCV000492771 pathogenic Lissencephaly; Microcephaly 2015-10-06 criteria provided, single submitter clinical testing
Counsyl RCV000007353 SCV000678042 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-06-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000007353 SCV000697978 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-11-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212733 SCV000806448 pathogenic not provided 2017-02-20 criteria provided, single submitter clinical testing
GeneKor MSA RCV000133576 SCV000821748 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000007353 SCV000838310 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212733 SCV000889554 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing
OMIM RCV000007353 SCV000027552 pathogenic Microcephaly, normal intelligence and immunodeficiency 2008-10-15 no assertion criteria provided literature only
OMIM RCV000007354 SCV000027553 risk factor Breast-ovarian cancer, familial 1 2008-10-15 no assertion criteria provided literature only
GeneReviews RCV000007353 SCV000494627 pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-02-02 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785438 SCV000924010 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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