rs199845467

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_002485.5(NBN):c.671G>A(p.Gly224Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,612,740 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 1 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 3.28

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.671G>A	p.Gly224Glu	missense_variant	Exon 6 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.671G>A	p.Gly224Glu	missense_variant	Exon 6 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250560

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135480

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

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:

0.0000795

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1460742

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726690

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

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:

0.0000576

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:5

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 224 of the NBN protein (p.Gly224Glu). This variant is present in population databases (rs199845467, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer and sarcoma (PMID: 27498913, 28135145, 29522266, 31206626, 36346689). ClinVar contains an entry for this variant (Variation ID: 141380). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:3

Dec 15, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NBN c.671G>A (p.Gly224Glu) variant has been reported in the published literature in individuals with breast cancer and in reportedly healthy individuals (PMIDs: 31206626 (2019), 29522266 (2018), 28135145 (2017), 26787654 (2016), 26315354 (2015), and 25186627 (2015)), as well as in breast cancer cases and reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). It was also reported in an affected individual with Lynch Syndrome with a pathogenic MSH2 variant (PMID: 33630411 (2021)). The frequency of this variant in the general population, 0.00012 (15/128658 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jul 19, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28135145, 26315354, 26787654, 27498913, 25186627, 29522266, 28873162) -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2

Aug 04, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the NBN gene demonstrated a sequence change, c.671G>A, in exon 6 that results in an amino acid change, p.Gly224Glu. This sequence change has been described in the gnomAD database with frequency of 0.012% in the non-Finnish European subpopulation (dbSNP rs199845467). The p.Gly224Glu change affects a moderately conserved amino acid residue located in a domain of the NBN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly224Glu substitution. This variant has been reported in individuals with cancer as well as in healthy controls (PMID: 28135145, 27498913, 26315354, 24894818). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly224Glu change remains unknown at this time. -

Sep 09, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NBN c.671G>A (p.Gly224Glu) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain (IPR032429) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250560 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. c.671G>A has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with a variety of cancers such as colorectal, breast and other tumors (example, Tung_2015, Yurgelun_2017, Ferrer-Avargues_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome and/or associated tumors. At-least one co-occurrence with another pathogenic variant has been reported (Ferrer-Avargues_2021, MSH2 c.942+2T>A), providing 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: 33630411, 25186627, 28135145). ClinVar contains an entry for this variant (Variation ID: 141380). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Jun 11, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G224E variant (also known as c.671G>A), located in coding exon 6 of the NBN gene, results from a G to A substitution at nucleotide position 671. The glycine at codon 224 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified in individuals with various cancer types as well as healthy controls, including individuals positive for pathogenic mutations in other genes concordant with clinical histories (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107Young EL et al. J. Med. Genet., 2016 06;53:366-76; Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095; Tung N et al. Cancer, 2015 Jan;121:25-33; Weitzel JN et al. Cancer, 2019 08;125:2829-2836; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Ferrer-Avargues R et al. Cancer Commun (Lond), 2021 03;41:218-228). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Aplastic anemia

Uncertain:1

Mar 17, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NBN-related disorder

Uncertain:1

Jun 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NBN c.671G>A variant is predicted to result in the amino acid substitution p.Gly224Glu. This variant has been reported in individuals with colorectal cancer (Yurgelun et al. 2017. PubMed ID: 28135145) and sarcoma ( Ballinger et al. 2016. PubMed ID: 27498913), as well as in healthy controls (Damiola et al. 2014. PubMed ID: 24894818; Ramus et al. 2015. PubMed ID: 26315354). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90983432-C-T) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141380/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

D;T;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.0

M;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.69

MVP

0.95

MPC

0.46

ClinPred

0.93

GERP RS

5.8

Varity_R

0.64

gMVP

0.77

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