chr8-89955298-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002485.5(NBN):​c.1382C>T​(p.Pro461Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 2.21
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1152547).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NBNNM_002485.5 linkc.1382C>T p.Pro461Leu missense_variant Exon 10 of 16 ENST00000265433.8 NP_002476.2 O60934

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NBNENST00000265433.8 linkc.1382C>T p.Pro461Leu missense_variant Exon 10 of 16 1 NM_002485.5 ENSP00000265433.4 O60934

Frequencies

GnomAD3 genomes
AF:
0.0000659
AC:
10
AN:
151822
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
251072
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135730
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461240
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
726934
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000659
AC:
10
AN:
151822
Hom.:
0
Cov.:
32
AF XY:
0.0000540
AC XY:
4
AN XY:
74124
show subpopulations
Gnomad4 AFR
AF:
0.000242
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000664
Hom.:
0
Bravo
AF:
0.0000982
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:3
Oct 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 461 of the NBN protein (p.Pro461Leu). This variant is present in population databases (rs367760321, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 461508). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Jul 05, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:2
Jul 29, 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.1382C>T, in exon 10 that results in an amino acid change, p.Pro461Leu. This sequence change has been described in the gnomAD database with a frequency of 0.032% in the African/African-American subpopulation (dbSNP rs367760321). The p.Pro461Leu 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.Pro461Leu substitution. This sequence change does not appear to have been previously described in individuals with NBN-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro461Leu change remains unknown at this time. -

May 23, 2022
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.1382C>T (p.Pro461Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251072 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1382C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (example, Tung_2015, Fonfria_2021). 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. Seven 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. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2
Sep 01, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 25186627, 34204722, 24894818, 33471991) -

Dec 02, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NBN c.1382C>T (p.Pro461Leu) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 25186627 (2015), 34204722 (2021), and 33471991 (2021); see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00032 (8/24904 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Apr 03, 2023
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 15, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Aplastic anemia Uncertain:1
Jan 31, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

NBN-related disorder Uncertain:1
Jun 13, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NBN c.1382C>T variant is predicted to result in the amino acid substitution p.Pro461Leu. This variant has been reported in an individual with breast cancer (Tung et al. 2015. PubMed ID: 25186627). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90967526-G-A) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/461508/). 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
0.10
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.22
T;T
Eigen
Benign
-0.071
Eigen_PC
Benign
0.062
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Uncertain
2.2
M;.
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Benign
0.041
Sift
Benign
0.084
T;T
Sift4G
Benign
0.18
T;T
Polyphen
0.0050
B;.
Vest4
0.18
MVP
0.72
MPC
0.071
ClinPred
0.11
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.052
gMVP
0.31

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.

Other links and lift over

dbSNP: rs367760321; hg19: chr8-90967526; COSMIC: COSV55377761; COSMIC: COSV55377761; API