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rs34767364

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002485.5(NBN):c.643C>T(p.Arg215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,613,094 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts 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. R215Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

11
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:13O:3

Conservation

PhyloP100: 1.63
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05029258).
BP6
Variant 8-89971232-G-A is Benign according to our data. Variant chr8-89971232-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6948.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=4, Benign=4, not_provided=3}. Variant chr8-89971232-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00204 (310/152148) while in subpopulation NFE AF= 0.00359 (244/67988). AF 95% confidence interval is 0.00322. There are 0 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NBNNM_002485.5 linkuse as main transcriptc.643C>T p.Arg215Trp missense_variant 6/16 ENST00000265433.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.643C>T p.Arg215Trp missense_variant 6/161 NM_002485.5 P1

Frequencies

GnomAD3 genomes
AF:
0.00204
AC:
310
AN:
152030
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000459
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00138
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00199
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00359
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00251
AC:
630
AN:
250856
Hom.:
3
AF XY:
0.00251
AC XY:
341
AN XY:
135642
show subpopulations
Gnomad AFR exome
AF:
0.000309
Gnomad AMR exome
AF:
0.00165
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00333
Gnomad NFE exome
AF:
0.00422
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00317
AC:
4624
AN:
1460946
Hom.:
11
Cov.:
30
AF XY:
0.00302
AC XY:
2195
AN XY:
726782
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00168
Gnomad4 ASJ exome
AF:
0.000192
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00274
Gnomad4 NFE exome
AF:
0.00380
Gnomad4 OTH exome
AF:
0.00234
GnomAD4 genome
AF:
0.00204
AC:
310
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.00207
AC XY:
154
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.000458
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00199
Gnomad4 NFE
AF:
0.00359
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00273
Hom.:
1
Bravo
AF:
0.00198
TwinsUK
AF:
0.00458
AC:
17
ALSPAC
AF:
0.00363
AC:
14
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00372
AC:
32
ExAC
AF:
0.00293
AC:
355
EpiCase
AF:
0.00349
EpiControl
AF:
0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:8Benign:13Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:1Uncertain:2Benign:4Other:2
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2006- -
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The NBN p.Arg215Trp variant was identified in 53 of 18583 proband chromosomes (frequency: 0.003) from Australian, North American, French Canadian, Macedonian, German, Belarusian, and Polish individuals or families with breast, ovarian or other cancers and was present in 19 of 15624 control chromosomes (frequency: 0.001) from healthy individuals (Damiola 2014, Desjardins 2009, Kostovska 2015, Bogdanova 2007, Steffen 2004, Ramus 2015, Kurian 2014). The variant was also identified in dbSNP (ID: rs34767364) as “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity including benign by Invitae, Color Genomics; likely benign by Ambry Genetics, ARUP Laboratories; uncertain significance by EGL Genetic Diagnostics, Genetic Services Laboratory-University of Chicago, Quest Diagnostics Nichols Institute San Juan Capistrano, Laboratory Corporation of America and Praxis fuer Humangenetik Tuebingen; pathogenic by GeneReviews and OMIM; and classification not provided by ITMI), Clinvitae (5x), LOVD 3.0 (1x), Zhejiang University Database (24x , co-occurring with pathogenic NBN variant c.657_661del/p.Lys219AsnfsX16), and was not identified in Cosmic. The variant was identified in control databases in 671 of 276666 chromosomes (3 homozygous) at a frequency of 0.002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 14 of 24000 chromosomes (freq: 0.0006), Other in 16 of 6452 chromosomes (freq: 0.002), Latino in 55 of 34344 chromosomes (freq: 0.002), European Non-Finnish in 502 (3 homozygous) of 126366 chromosomes (freq: 0.004), Ashkenazi Jewish in 3 of 10136 chromosomes (freq: 0.0003), Finnish in 79 of 25738 chromosomes (freq: 0.003), and South Asian in 2 of 30780 chromosomes (freq: 0.00007); it was not in the East Asian population. There is conflicting evidence in the literature as studies utilizing breast cancer cell lines from a heterozygous breast cancer patient carrying the variant and a truncating BRCA1 variant showed a 70% reduction of NBN protein expression, which was not seen in a BRCA1 cell line with wildtype NBN (Bogdanova 2007, Schroder-Heurich 2014). Seemanova et al (2005) also describe a dosage effect in twin boys affected with Nijmegen breakage syndrome, who are compound heterozygotes (with the founder mutation NBN 657del5), whereby the variant produced full length nibrin, but addition of the nonpolar Trp may still be associated with protein instability. In a large meta-analysis encompassing 60 independent publications, the variant was related to susceptibility to all cancers, but no significant risk was observed for breast cancer (Gao 2013). The p.Arg215 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 24, 2017- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Uncertain significance and reported on 05-24-2017 by Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not provided, no classification providedliterature onlyGeneReviews-- -
Likely benign, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 10, 2020- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
not provided Uncertain:4Benign:3
Uncertain significance, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 07, 2018- -
Benign, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 21, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 26, 2023The NBN c.643C>T; p.Arg215Trp variant (rs34767364) is reported in the literature in individuals affected with melanoma, breast/ovarian cancer, and Nijmegen breakage syndrome (Berardinelli 2013, Bhai 2021, de Oliveira 2022, Gao 2013, Seemanova 2006). Meta-analysis suggested a cancer-risk of this variant with an odds ratio of 1.7 (Gao 2013). In vitro functional analyses demonstrate a modifying deleterious effect when co-occurring with a pathogenic variant in trans (Seemanova 2006). A breast cancer cell line carrying this variant in hemizygous state has impaired function of NBN (Schroder-Heurich 2014). Additionally, heterozygous p.Arg215Trp B cells were reported to have comparable NBN function and radiosensitivity compared to control cells (Dzikiewicz-Krawczyk 2012). This variant is also reported in ClinVar (Variation ID: 6948) and is found in the non-Finnish European population with an allele frequency of 0.4% (521/128796 alleles, including 3 homozygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.343). Due to conflicting information, the clinical significance of the NBN c.643C>T; p.Arg215Trp variant is uncertain at this time. References: Berardinelli et al. NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review. Curr Genomics. 2013 Nov;14(7):425-40. PMID: 24396275. Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. de Oliveira JM et al. The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. Eur J Hum Genet. 2022 Jul;30(7):818-823. PMID: 35534704. di Masi A, et al. The R215W mutation in NBS1 impairs gamma-H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients. Biochem Biophys Res Commun. 2008 May 9;369(3):835-40. PMID: 18328813. Dzikiewicz-Krawczyk A et al. Impact of heterozygous c.657-661del, p.I171V and p.R215W mutations in NBN on nibrin functions. Mutagenesis. 2012 May;27(3):337-43. PMID: 22131123. Gao P et al. Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. Mutagenesis. 2013 Nov;28(6):683-97. PMID: 24113799. Schroder-Heurich B et al. Functional deficiency of NBN, the Nijmegen breakage syndrome protein, in a p.R215W mutant breast cancer cell line. BMC Cancer. 2014 Jun 13;14:434. PMID: 24928521. Seemanova E et al. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. 2006 Mar;43(3):218-24. PMID: 16033915. -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024NBN: BP4, BS2 -
Uncertain significance, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Hereditary cancer-predisposing syndrome Uncertain:2Benign:3
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsSep 05, 2017- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 28, 2019This 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneKor MSAAug 01, 2018- -
Uncertain significance, no assertion criteria providedclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Sep 27, 2021- -
Likely benign, criteria provided, single submittercurationSema4, Sema4May 03, 2021- -
not specified Benign:2Other:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 12, 2021- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 01, 2019Variant summary: NBN c.643C>T (p.Arg215Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 269024 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the frequency in general population is in sub-polymorphic range and these data alone cannot rule out the possibility that it can still have a role as a risk variant in disease, although it has not been reported to have a considerably significant association with other forms of cancer (Taylor_2003, Hebbring_2006, Bogdanovaas_2008, Dzikiewicz-Krawczyk_2012, and Ramus_2014). This is consistent with studies reporting 95% CI around the OR to include 1.0, thereby providing little to no confidence on the strength of the assertions. Specifically, this variant was not significantly associated with increased risk for breast cancer (Bogdanova_2008) (adjusted OR = 1.9, 95%CI 0.84.6, p = 0.18) or prostate cancer (Hebbring_Cancer Epidemiol Biomarkers_2006) (OR = 1.24, 95CI 0.31-4.99, p = 0.77). Functional studies in compound heterozygotes with the 675del5 mutation have shown this variant to affect DNA repair and protein stability, however it is difficult from those studies to make conclusions about the effect of NBN Arg215Trp alone (Seemanova_2006, Bogdanova_2008, di Masi_2008, Mendez_2012). In addition, the variant did not increase chromosome breakage in cells (Seemanova_2006). It was found in a triple negative breast cancer cell line with alternate molecular basis for disease attributed to BRCA1, p.R715X mutation. Although the tumor specimen showed LOH for this NBN variant, the tumor histological characteristics and sensitivity of the cell line to PARP inhibitors can be attributed to the BRCA1 variant. Therefore, the overall implication of these functional data in causation of the NBS or cancer phenotype needs to be further clarified or is unknown (Schroder-Heurich_2014). Meanwhile, functional assays from heterozygous carriers of this variant have also shown the evidences of functional impairment (such as reduced expression of full-length nibrin, impairment in binding with gamma-H2AX and reduction in DNA-DSB rejoining) [Seemanova_2006, di Masi_2006, Dzikiewicz-Krawczyk_2012, and Schroder-Heurich_2014]. From a cell line that also carried BRCA1 p.R1751X, Schroder-Heurich_2014, reports that the (i) cells were highly radiosensitive, susceptible to apoptosis and were deficient in the formation of NBN foci, (ii) NBN was observed only at 30-40% of wildtype levels in the cells; and (iii) there was also evidence for some impairment in the formation of H2AX, MDC1, and 53BP1 foci after irradiation; and these foci appeared smaller and irregular compared with repair foci in wild-type cells, although ATM signaling was largely unaffected. The authors report that these functional consequences related to NBN are not explained by the BRCA1 mutation. This variant has been found in two severely NBS-affected siblings who were compound heterozygous for this variant and 657del5 (Seemanova_2006), although without increased chromosome breakage. Co-occurrences with other pathogenic variants have been reported (TP53 c.783-1G>A; BRCA2 c.8537_8538del, p.Glu2846Glyfs*22) (Yurgelun_2017, Tung_2016), providing supporting evidence for a benign role. 13 ClinVar submitters (evaluation after 2014) classified the variant as benign (1x), likely be -
NBN-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 14, 2020This 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
0.13
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
0.040
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D;T;.;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Benign
0.097
N
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.050
T;T;T;T
MetaSVM
Uncertain
0.054
D
MutationAssessor
Uncertain
2.4
M;.;.;.
MutationTaster
Benign
9.0e-8
A;A
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-4.1
D;D;D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.015
D;D;D;D
Sift4G
Benign
0.14
T;T;T;.
Polyphen
1.0
D;.;.;.
Vest4
0.63
MVP
0.92
MPC
0.41
ClinPred
0.049
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.13
gMVP
0.56

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.

Other links and lift over

dbSNP: rs34767364; hg19: chr8-90983460; COSMIC: COSV55371278; API