rs1225178489

chr8-89970428-A-Cchr8-89970428-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002485.5(NBN):c.832T>G(p.Ser278Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S278P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 1.55

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine; by ATM (size 0) in uniprot entity NBN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2260614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.832T>G	p.Ser278Ala	missense_variant	7/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.832T>G	p.Ser278Ala	missense_variant	7/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251342 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 12, 2022	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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 25, 2016

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. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

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. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.29	B;.
Vest4		0.42
MutPred		0.34		Loss of helix (P = 0.0376);.;
MVP		0.79
MPC		0.072
ClinPred		0.77	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1225178489; hg19: chr8-90982656;