ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.284A>G (p.Asp95Gly)

gnomAD frequency: 0.00003  dbSNP: rs545276922
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130482 SCV000185351 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-12 criteria provided, single submitter clinical testing The p.D95G variant (also known as c.284A>G), located in coding exon 3 of the NBN gene, results from an A to G substitution at nucleotide position 284. The aspartic acid at codon 95 is replaced by glycine, an amino acid with similar properties. This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This variant was reported in 17/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000459979 SCV000553099 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2022-09-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 95 of the NBN protein (p.Asp95Gly). This variant is present in population databases (rs545276922, gnomAD 0.007%). 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: 141816). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (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 RCV000486308 SCV000569033 uncertain significance not provided 2023-01-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26315354, 29522266, 24894818)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193649 SCV001362626 uncertain significance not specified 2019-01-14 criteria provided, single submitter clinical testing Variant summary: NBN c.284A>G (p.Asp95Gly) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 277122 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (3.6e-05 vs 0.0025), allowing no conclusion about variant significance. c.284A>G has been reported in the literature in individuals affected with breast cancer (Hauke_2018). These report(s) 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV000459979 SCV002045246 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000459979 SCV004031170 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2023-05-23 criteria provided, single submitter clinical testing The NBN c.284A>G (p.Asp95Gly) missense change has a maximum subpopulation frequency of 0.0077% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in a large case-control study of breast cancer in 17 of 60,466 cases and 5 of 53,461 controls (PMID: 33471991). To our knowledge, this variant has not been reported in individuals with Nijmegan breakage syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics RCV003474763 SCV004199556 uncertain significance Aplastic anemia 2024-03-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV000459979 SCV001461777 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-09-16 no assertion criteria provided clinical testing

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