Submissions for variant NM_002485.5(NBN):c.123del (p.Ser42fs)

gnomAD frequency: 0.00001  dbSNP: rs587781891

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130227	SCV000185067	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-02	criteria provided, single submitter	clinical testing	The c.123delC pathogenic mutation, located in coding exon 2 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 123, causing a translational frameshift with a predicted alternate stop codon (p.S42Afs*7). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466522	SCV000553077	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser42Alafs*7) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs587781891, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 141631). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000482320	SCV000569358	likely pathogenic	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Identified in a patient with prostate cancer (Matejcic 2020); This variant is associated with the following publications: (PMID: 26786923, 29915322, 30612635, 28152038, 32832836)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000466522	SCV002041643	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-16	criteria provided, single submitter	clinical testing	Variant summary: NBN c.123delC (p.Ser42AlafsX7) 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. Truncations downstream of this position have been classified as pathogenic both in settings of Nijmegen breakage syndrome and susceptibility to cancer by our laboratory and have been reported in the HGMD database. The variant allele was found at a frequency of 4e-06 in 251430 control chromosomes (gnomAD). c.123delC has been reported in the literature mainly in individuals affected with breast cancer, ovarian cancer and prostate cancer (examples: Zuntini_2021, Bishop_2020, Long_2019, Matejci_2019, Mijuskovic_2018, and LaDuca_2016) but not as a homozygous or compound heterozygous genotype in settings of autosomal recessive Nijmegen Breakage Syndrome. Although these reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome, the risk of breast and prostate cancers among heterozygous carriers of pathogenic alleles in the NBN gene is well understood (example, Steffen_2004, Seemanova_2007, Cybulski_2013). 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 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for phenotypes of Nijmegen breakage syndrome and NBN-related cancers.
Genome-Nilou Lab	RCV000466522	SCV002045381	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460916	SCV004191971	pathogenic	Aplastic anemia	2024-03-14	criteria provided, single submitter	clinical testing