8-89978298-C-T

Position:

chr8-89978298-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_002485.5(NBN):c.506G>A(p.Arg169His) variant causes a missense change. The variant allele was found at a frequency of 0.0000233 in 1,590,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 4.29

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_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37839478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	5/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	5/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251268

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1438682

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

717092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000220

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000860

Hom.:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 169 of the NBN protein (p.Arg169His). This variant is present in population databases (rs776134250, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or Nijmegen breakage syndrome. However, in at least one individual pathogenic alleles were also identified in the RAD50 gene, which suggests that this c.506G>A variant was not the primary cause of disease. (PMID: 19409520, 29522266, 30287823). ClinVar contains an entry for this variant (Variation ID: 186682). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2023	The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the NBN gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in an individual suspicious for Nijmegen breakage syndrome (NBS); however, the patient was found to carry biallelic RAD50 mutations, and the authors concluded these were the cause of his NBS-like phenotype (Waltes R et al. Am. J. Hum. Genet. 2009 May;84:605-16). Additionally, this alteration was observed in with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083), and with a carrier frequency of 0.00013 in 7,636 unselected prostate cancer patients and not detected in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and was reported in 7/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 11, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 21, 2021

Variant summary: NBN c.506G>A (p.Arg169His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.506G>A has been reported in the literature in an individual with clinical features suggestive of Nijmegen Breakage Syndrome; however, clinical presentation in the patient was likely due to presence of bi-allelic mutations in the RAD50 gene (c.3277C>T/c.3939A>T, p.R1093X/p.X1313YextX*66; Waltes_2009). Additionally, it was reported as a VUS in a Japanese patient with breast cancer (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aplastic anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 01, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Hauke 2018, Momozawa 2018); Observed in an individual with symptoms overlapping with Nijmegen Breakage syndrome, however, this individual also carried compound heterozygous truncating variants in the RAD50 gene, to which the authors attributed the patient's phenotype (Waltes 2009); This variant is associated with the following publications: (PMID: 19409520, 30287823, 29522266, 32501622) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;T;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

L;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Benign

0.21

Sift

Benign

0.033

D;D;D;D

Sift4G

Uncertain

0.010

D;D;.;D

Polyphen

0.82

P;.;.;.

Vest4

0.49

MVP

0.87

MPC

0.091

ClinPred

0.18

GERP RS

5.1

Varity_R

0.14

gMVP

0.67

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

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