rs200287925

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_002485.5(NBN):c.127C>T(p.Arg43*) 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:15U:1

Conservation

PhyloP100: 1.07

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
idiopathic aplastic anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 142203.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.127C>T	p.Arg43*	stop_gained	Exon 2 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.127C>T	p.Arg43*	stop_gained	Exon 2 of 16	1	NM_002485.5	ENSP00000265433.4

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

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251426

AF XY:

0.0000147

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1111874

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000641

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:15Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Pathogenic:8

Apr 18, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 04, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 05, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous nonsense variant was identified, NM_002485.4(NBN):c.127C>T in exon 2 of 16 of the NBN gene. (NB: This variant is non-coding in an alternative transcript). This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 43 of the protein; NP_002476.2(NBN):p.(Arg43*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a global population frequency of 0.003% (8 heterozygotes; 0 homozygotes) with a European (Finnish) sub-population frequency of 0.02%. The variant has been previously reported in patients with breast cancer (ClinVar, Tessitore, A. et al. (2003), LaDuca, H. et al. (2014), Young, E. et al. (2016), Thompson, E. et al. (2016), Tung, N. et al. (2016)). Other variants predicted to cause NMD have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Pathogenic:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal history of breast cancer or glioblastoma (PMID: 24894818, 26786923, 26976419, 32318955, 26689913); 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, 33344249, 34887416, 34308104, 36451132) -

Dec 03, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Dec 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Based on the available evidence, the clinical significance of this variant remains unclear. -

Feb 18, 2022

Sema4, Sema4

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency

Pathogenic:1

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aplastic anemia

Pathogenic:1

Mar 01, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.70

PhyloP100

1.1

Vest4

0.89

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over