chr8-89958813-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002485.5(NBN):c.1036G>A(p.Val346Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,912 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. V346L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:11

Conservation

PhyloP100: 0.679

Publications

8 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062656403).

BP6

Variant 8-89958813-C-T is Benign according to our data. Variant chr8-89958813-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127854.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000144 (22/152332) while in subpopulation EAS AF = 0.00289 (15/5184). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1036G>A	p.Val346Met	missense_variant	Exon 9 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1036G>A	p.Val346Met	missense_variant	Exon 9 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000302

AC:

AN:

251374

AF XY:

0.000287

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000814

AC:

119

AN:

1461580

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33462

American (AMR)

AF:

0.000112

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00154

AC:

AN:

39696

South Asian (SAS)

AF:

0.000290

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111758

Other (OTH)

AF:

0.0000662

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000144

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00289

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000996

Hom.:

Bravo

AF:

0.000159

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Dec 27, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 25, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23525077, 26976419, 27443514, 23555315) -

Jan 11, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency

Uncertain:1Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 03, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Nov 05, 2020

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 28, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 27, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 27, 2018

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 26, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NBN c.1036G>A (p.Val346Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251374 control chromosomes, predominantly at a frequency of 0.0033 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1036G>A has been reported in the literature in individuals affected with breast cancer, endometrial cancer and in unaffected controls (example, Haiman_2013, Tung_2016, Ring_2016, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome or with any of the NBN associated tumors. At-least two co-occurrences with other pathogenic variants have been observed at our laboratory (APC c.1206_1207delTG, p.Glu403AsnfsX15; BRCA2 c.6405_6409delCTTAA, p.Asn2135LysfsX3), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23555315, 26976419, 27443514, 30287823). Fourteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=9) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Aplastic anemia

Uncertain:1

Nov 23, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NBN p.Val346Met variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs200297914) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Invitae and uncertain significance by GeneDx, Ambry Genetics, EGL Genetic Diagnostics and Laboratory Corporation of America), Clinvitae (4x), Cosmic (1x in an adenocarcinoma of the oesophagus), and not identified in LOVD 3.0 and Zhejiang University Database. The variant was identified in control databases in 77 of 277100 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 3 of 34386 chromosomes (freq: 0.00009), European Non-Finnish in 2 of 126628 chromosomes (freq: 0.00002), East Asian in 62 of 18866 chromosomes (freq: 0.003), and South Asian in 10 of 30782 chromosomes (freq: 0.0003); it was not observed in the African, Other, Ashkenazi Jewish and Finnish populations. The p.Val346 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of the variant Met to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Prostate cancer

Benign:1

Jun 22, 2020

ACT Genomics,

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The allele frequency of this variant c.1036G>A (p.Val346Met) is 0.003 in East Asian of gnomAD Exomes and 0.002 in East Asian in 1000 Genomes.Â There is a small physicochemical difference between valine and methionine, which is not likely to impact secondary protein structure as these residues share similar properties. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign. -

NBN-related disorder

Benign:1

Feb 02, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.092

T;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;.

PhyloP100

0.68

PrimateAI

Benign

0.25

PROVEAN

Benign

0.47

N;N

REVEL

Benign

0.070

Sift

Benign

0.16

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0020

B;.

Vest4

0.058

MVP

0.50

MPC

0.067

ClinPred

0.030

GERP RS

3.1

Varity_R

0.020

gMVP

0.15

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over