Submissions for variant NM_002485.5(NBN):c.481-2A>T

gnomAD frequency: 0.00001  dbSNP: rs751567476

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523496	SCV000619808	likely pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with esophagogastric cancer (Ku et al., 2021); This variant is associated with the following publications: (PMID: 29922827, 16415040, 9590180, 34251444)
Ambry Genetics	RCV000569604	SCV000662681	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The c.481-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 5 in the NBN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707500	SCV000836601	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the NBN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs751567476, gnomAD 0.02%). 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: 451148). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000707500	SCV000919849	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2018-03-12	criteria provided, single submitter	clinical testing	Variant summary: NBN c.481-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 245872 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (1.2e-05 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.481-2A>T in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sema4, Sema4	RCV000569604	SCV002536688	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002497023	SCV002811655	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2022-01-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470656	SCV004199549	likely pathogenic	Aplastic anemia	2024-03-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523496	SCV004222136	likely pathogenic	not provided	2022-12-03	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal NBN mRNA splicing. The frequency of this variant in the general population, 0.000012 (3/250980 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a homozygous state in an individual with stomach cancer (PMID: 34251444 (2021)). Based on the available information, this variant is classified as likely pathogenic.
Natera, Inc.	RCV000707500	SCV001461773	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing