rs200287925

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_002485.5(NBN):c.127C>T(p.Arg43Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R43R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

NBN
NM_002485.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 1.07

Variant links:

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]

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 8-89982766-G-A is Pathogenic according to our data. Variant chr8-89982766-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142203.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Pathogenic=5, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.127C>T	p.Arg43Ter	stop_gained	2/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.127C>T	p.Arg43Ter	stop_gained	2/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251426

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000185

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000469

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Arg43*) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs200287925, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with triple negative breast cancer (PMID: 24763289, 26976419). ClinVar contains an entry for this variant (Variation ID: 142203). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2018	The p.Arg43X variant in NBN has been not been reported in individuals with Nijme gen breakage syndrome. However, it has reported in 1 individual with hereditary cancer and two individuals with breast cancer (LaDuca 2014, Tung 2016, Thompson 2016) and has been reported in ClinVar (Variation ID: 142203). The variant has b een identified in 4/22288 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200287925). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 43 which is predicted to lead to a tru ncated or absent protein. Loss of function of the NBS gene is an established dis ease mechanism in Nijmegen breakage syndrome. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg43X va riant is likely pathogenic for Nijmegen breakage syndrome. in an autosomal reces sive manner based upon predicted impact to the protein and absence from controls ,. ACMG/AMP Criteria applied: PVS1; PM2. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2022	Variant summary: NBN c.127C>T (p.Arg43X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251426 control chromosomes (gnomAD). c.127C>T has been reported in the literature in individuals affected with various cancers, including those of the breast and brain (e.g. Damiola_2014, LaDuca_2014, Lu_2015, Thompson_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, six as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal history of breast cancer or glioblastoma (Damiola et al., 2014; Lu et al., 2015; Thompson et al., 2016; Tung et al., 2016; Zeng et al., 2020); This variant is associated with the following publications: (PMID: 24763289, 29922827, 29625052, 25032700, 26976419, 26786923, 19523210, 24894818, 26787654, 29555771, 26689913, 32318955, 31980526, 34072463, 32427313, 33804961, 35257886, 12433983, 11279524, 12708449, 19105185, 36988593, 36451132, 33344249, 34887416, 34308104) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 03, 2019	DNA sequence analysis of the NBN gene demonstrated a sequence change, c.127C>T, which results in the creation of a premature stop codon at amino acid position 43, p.Arg43*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NBN protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a population frequency of 0.018% in Finnish subpopulation (dbSNP rs200287925). This sequence change has previously been described in a patient with triple-negative breast cancer and a family history of lung cancer, exocrine pancreatic cancer and CNS tumor (PMID: 26976419). Additionally it has also been identified in two patients with personal and/or family history of breast cancer but limited clinical information was provided (PMID: 26786923, PMID: 29555771). Truncating variants in the NBN gene are known to be pathogenic. These collective evidences indicate that this sequence change is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2023	The p.R43* variant (also known as c.127C>T), located in coding exon 2 of the NBN gene, results from a C to T substitution at nucleotide position 127. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of theNBN gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas MA et al. Science. 2015 May 8;348(6235):666-9; Lindeboom RGH et al. Nat. Genet. 2016 Oct;48(10):1112-8; Rhee JK et al. Sci. Rep. 2017 May 10;7(1):1653). Re-initiation on a downstream methionine would disrupt the forkhead-associated domain (FHA) which has been implicated in NBN function (Zhao S et al. Nucleic Acids Res. 2002 Nov;30:4815-22). However, the exact functional impact of this particular alteration is unknown at this time. This alteration has been reported in patients with breast cancer (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58; Thompson ER et al. J. Clin. Oncol. 2016 May;34:1455-9; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). It has also been identified in trans with a possible deleterious variant in an individual without features of Nijmegen breakage syndrome (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 18, 2022	- -

Aplastic anemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 24, 2023

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.70

MutationTaster

Benign

1.0

A;D

Vest4

0.89

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over