Submissions for variant NM_002485.5(NBN):c.832T>G (p.Ser278Ala)

dbSNP: rs1225178489

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589829	SCV000697981	uncertain significance	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: The c.832T>G in NBN gene is a missense variant that involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is absent from the broad control population datasets from ExAC, suggesting this variant is not a common polymorphism. The variant has been reported as a germline mutation in one patient presented with a clinical characteristics suggestive of Lynch Syndrome. Ser278 is a direct substrate for ATM kinase, however, the effect of phosphorylation or lack thereof in the functional studies performed in vitro and in vivo showed contradicting results, perhaps, due to limitations of the technical approaches. It is possible, that the variant of interest is a mild mutation and may play role in radiation dose dependency. However further investigation is needed to support this proposition. The variant of interest has not been reported by reputable databases/clinical laboratories. Taken together, the variant was classified as Variant of Uncertain until more information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701071	SCV000829854	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 278 of the NBN protein (p.Ser278Ala). This variant is present in population databases (no rsID available, gnomAD no frequency). 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: 496166). 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"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NBN function (PMID: 10839544, 21664921). 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.
Mendelics	RCV003492114	SCV001137665	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000701071	SCV002044773	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000772494	SCV002675325	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-31	criteria provided, single submitter	clinical testing	The p.S278A variant (also known as c.832T>G), located in coding exon 7 of the NBN gene, results from a T to G substitution at nucleotide position 832. The serine at codon 278 is replaced by alanine, an amino acid with similar properties. This residue is phosphorylated by ATM in response to DNA damage, and has been demonstrated to be involved in S phase activation (Zhao S et al. Nature 2000 May; 405(6785):473-7). S278A mutants are unable to hyperphosphorylate RPA following hydroxyurea treatment, indicating its role in ATR signaling (Manthey KC et al. J. Cell. Sci. 2007 Dec;120(Pt 23):4221-9). Using a knock-in model, the mouse equivalent of S278A did not effect mouse development, but was found to play a role in regulating the activation of Chk2 and Smc1 in response to intermediate and high doses of ionizing radiation (Li and Wang. Mech. Ageing Dev. 2011 Aug;132(8-9):382-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355653	SCV001550597	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Ser278Ala variant was identified in ClinVar (classified as uncertain significance by Invitae and Integrated Genetics/Laboratory Corporation of America). The variant was not identified in dbSNP, or LOVD 3.0. The variant was identified in control databases in 1 of 246118 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the “Other” population in 1 of 5480 chromosomes (freq: 0.0002); it was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser278Ala variant was identified in experimental functional studies, where human lymphoblasts expressing the variant show a completely normal CHEK2 phosphorylation and exhibit normal CHEK2 activation after DNA damage (Lee 2003, Zhao 2000). Variant at this loci does not affect development, but compromises the CHEK2 and SMC1 phosphorylation after DNA damage in mice (Li 2011). The p.Ser278 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000701071	SCV002078625	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-05-02	no assertion criteria provided	clinical testing