Submissions for variant NM_002485.5(NBN):c.1405G>T (p.Asp469Tyr)

gnomAD frequency: 0.00025  dbSNP: rs148205441

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129788	SCV000184597	likely benign	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000167890	SCV000218536	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 469 of the NBN protein (p.Asp469Tyr). This variant is present in population databases (rs148205441, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 134873). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000588734	SCV000279206	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a woman with breast cancer and in a child with glioma (Zhang et al., 2015; Lovejoy et al., 2018); This variant is associated with the following publications: (PMID: 26580448, 24728327, 26315354, 18281469, Lovejoy2018)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121613	SCV000697946	uncertain significance	not specified	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1405G>T (p.Asp469Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 252750 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (4.7e-05 vs 0.0025), allowing no conclusion about variant significance. c.1405G>T has been reported in the literature in settings of multigene panel testing among individuals with cancers and in unaffected controls (example, Ramus_2015, Wang_2008, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign, n=1; VUS, n=10). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003389699	SCV000806411	uncertain significance	NBN-related condition	2023-01-25	criteria provided, single submitter	clinical testing	The NBN c.1405G>T variant is predicted to result in the amino acid substitution p.Asp469Tyr. This variant has been reported as a germline variant in a pediatric patient with low grade glioma (Zhang et al. 2015. PubMed ID: 26580448 Table S4b) and as a somatic variant in pancreatic cancer (Wang et al. 2008. PubMed ID: 18281469 Table S3 ) but also was reported as a germline variant in healthy controls (Bodian et al. 2014. PubMed ID: 24728327; Ramus et al 2015. PubMed ID: 26315354 Table S4). This variant is reported in 0.066% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90965912-C-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from Likely benign to Uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/134873/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mendelics	RCV000167890	SCV000838302	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588734	SCV000889549	uncertain significance	not provided	2017-10-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000167890	SCV002045915	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225383	SCV002505287	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129788	SCV002536598	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	curation
Baylor Genetics	RCV003474728	SCV004199524	uncertain significance	Aplastic anemia	2023-10-17	criteria provided, single submitter	clinical testing
ITMI	RCV000121613	SCV000085811	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000167890	SCV001456600	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing