ClinVar Miner

Submissions for variant NM_001024688.2(NBN):c.896del (p.Pro299fs) (rs587781969)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130355 SCV000185206 pathogenic Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000220768 SCV000279248 pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing This deletion of one nucleotide is denoted NBN c.1142delC at the cDNA level and p.Pro381GlnfsX23 (P381QfsX23) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGGC[delC]AAAAG. The deletion causes a frameshift, which changes a Proline to a Glutamine at codon 381, and creates a premature stop codon at position 23 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. NBN c.1142delC has been observed with a pathogenic founder variant in individuals with Nijmegen Breakage syndrome (Varon 1998, Bakhshi 2003) and in individuals with a personal history of breast and/or ovarian cancer (Walsh 2011, Ramus 2015, Desmond 2015). We consider this variant to be pathogenic.
Invitae RCV000007358 SCV000287446 pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro381Glnfs*23) in the NBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587781969, ExAC 0.005%). This variant has been reported in individuals affected with Nijmegen breakage syndrome (PMID: 9590180, 10799436, 12621246), as well as breast and/or ovarian cancer (PMID: 22006311, 24549055, 26315354). ClinVar contains an entry for this variant (Variation ID: 141731). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000220768 SCV000609313 likely pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Counsyl RCV000007358 SCV000678049 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-05-16 criteria provided, single submitter clinical testing
Color RCV000130355 SCV000685695 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220768 SCV000889542 pathogenic not provided 2017-10-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000007358 SCV001337953 pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-01-14 criteria provided, single submitter clinical testing Variant summary: NBN c.1142delC (p.Pro381GlnfsX23) 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 249986 control chromosomes (gnomAD). c.1142delC has been reported in the literature in multiple individuals affected with Nijmegen Breakage Syndrome (e.g. Bakshi_2003, Varon_1998) as well as in breast and/or ovarian cancer patients (Ramus_2015, Walsh_2011, Carter_2018). These data indicate that the variant is very likely to be associated with disease. No Nibrin protein expression was detected in a cell line derived from a compound heterozygous patient who harbored this variant and another truncating variant (Bakshi_2003). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000007358 SCV000027557 pathogenic Microcephaly, normal intelligence and immunodeficiency 1998-05-01 no assertion criteria provided literature only
GeneReviews RCV000007358 SCV000494637 not provided Microcephaly, normal intelligence and immunodeficiency no assertion provided literature only

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