rs61754966
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_002485.5(NBN):c.511A>G(p.Ile171Val) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,593,902 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 5 hom. )
Consequence
NBN
NM_002485.5 missense
NM_002485.5 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 4.37
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=0.037225217).
BP6
Variant 8-89978293-T-C is Benign according to our data. Variant chr8-89978293-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6946.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, not_provided=1, Benign=2, Uncertain_significance=15}. Variant chr8-89978293-T-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00139 (212/152314) while in subpopulation NFE AF= 0.00254 (173/68022). AF 95% confidence interval is 0.00223. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NBN | NM_002485.5 | c.511A>G | p.Ile171Val | missense_variant | 5/16 | ENST00000265433.8 | NP_002476.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NBN | ENST00000265433.8 | c.511A>G | p.Ile171Val | missense_variant | 5/16 | 1 | NM_002485.5 | ENSP00000265433 | P1 |
Frequencies
GnomAD3 genomes 0.00139 AC: 212AN: 152196Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00120 AC: 301AN: 251288Hom.: 0 AF XY: 0.00117 AC XY: 159AN XY: 135832
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GnomAD4 exome AF: 0.00112 AC: 1618AN: 1441588Hom.: 5 Cov.: 28 AF XY: 0.00114 AC XY: 821AN XY: 718462
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GnomAD4 genome 0.00139 AC: 212AN: 152314Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107AN XY: 74472
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:15Benign:9Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 27, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2021 | This variant is associated with the following publications: (PMID: 21811815, 11325820, 30306255, 17695489, 28374160, 30651582, 31422574, 21698754, 19813148, 25862857, 23317186, 22373003, 16474176, 21436738, 19629396, 21472885, 19393249, 24396275, 25712764, 25619955, 15279809, 18056440, 15338273, 16810201, 26083025, 25980754, 19908051, 17899368, 19523210, 24093751, 18280732, 24113799, 24728327, 24830725, 22131123, 26722329, 27621404, 18049891, 28261280, 27616075, 28376765, 27153395, 28591191, 28076423, 28107384, 29335925, 31159747, 32019277, 30590007, 31278556, 31263571, 32566746) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 16, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 07, 2017 | The NBN c.511A>G;p.Ile171Val variant has been published in the medical literature in individuals with various cancers and has been shown to be associated with increased cancer development risk (Desjardins 2009, Gao 2013, Grajkowska 2009, Kaluzna 2015, Mosor 2013, Nowak 2008, Shimada 2004, Varon 2001). However, this variant has also been described as occurring at a similar frequency in affected and unaffected individuals and shown to have no significant association with cancer risk (Zhang 2012). The variant is listed in the ClinVar database (Variation ID: 6946) and the dbSNP variant database (rs61754966) with an allele frequency of 0.123 percent (16/12990 alleles) in the Exome Variant Server and 0.1509 percent (418/277070 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved among species, is predicted to reside in a critical functional domain, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Some functional studies do show a significant functional impairment, while others show no significant change (Dzikiewicz 2012, Yamamoto 2014). Due to conflicting information, it is unclear if this variant is benign or a low penetrance pathogenic allele. Therefore, the clinical significance of this variant cannot be determined with certainty. If this variant is later determined to be pathogenic, this individual may be at increased risk for development of breast cancer (OMIM#602667). References: Desjardins S et al. Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer. BMC Cancer. 2009 Jun 12;9:181. 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. 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. Grajkowska W et al. Ganglioglioma associated with alterations of NBN gene. A case report. Folia Neuropathol. 2009;47(3):278-83. Kaluzna EM et al. Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development. Oncol Lett. 2015 Nov;10(5):3300-3304. Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017 Jan 1;140(1):95-102. Mosor M et al. Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia. BMC Cancer. 2013 Oct 5;13:457. Nowak J et al. Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours. Eur J Cancer. 2008 Mar;44(4):627-30. Shimada H et al. First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability. Hum Genet. 2004 Oct;115(5):372-6. Varon R et al. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 2001 May 1;61(9):3570-2. Yamamoto Y et al. A rare polymorphic variant of NBS1 reduces DNA repair activity and elevates chromosomal instability. Cancer Res. 2014 Jul 15;74(14):3707-15. Zhang ZH et al. Current evidence on the relationship between two polymorphisms in the NBS1 gene and breast cancer risk: a meta-analysis. Asian Pac J Cancer Prev. 2012;13(11):5375-9. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 09, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | NBN: BP4, BS1:Supporting - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
| Uncertain significance, criteria provided, single submitter | research | Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2022 | 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. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 20, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneID Lab - Advanced Molecular Diagnostics | Sep 07, 2017 | - - |
Microcephaly, normal intelligence and immunodeficiency Uncertain:3Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 03, 2020 | - - |
not specified Uncertain:1Benign:1Other:1
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2019 | Variant summary: NBN c.511A>G (p.Ile171Val) results in a conservative amino acid change located in the BRCT domain of 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 0.0016 in 287466 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 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. c.511A>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer, various forms of leukemia and solid tumors (example Taylor_2003, Bogdanova_2008, Grajkowska_2009, Haiman_2013, Kaluzna_2015, Kim_2015, Ramus_2015). Several of these predate the emergence of large control datasets such as ExAC and gnomAD. Predominantly, these report(s) do not provide unequivocal conclusions about the association of the variant with Hereditary Breast and Ovarian Cancer. Furthermore, reports of association with other forms of leukemia and solid tumors have not been firmly established. Co-occurrences with other pathogenic variant(s) in multiple genes have been reported in the literature as well as in our own testing experience. Specifically, BRCA1 c.3700_3704delGTAAA, p.Val1234Glnfs (Domagala_2015); CHEK2 c.444+1G>A (Domagala_2015; BRCA2 c.6952C>T, p.Arg2318X (Internal testing); BRCA1, not specified; and PALB2, not specified (Koczkowska_2018). These co-occurrences provide additional supporting evidence for a benign role. Multiple publications provide conflicting experimental evidence evaluating an impact on protein function. Most report no difference in measures of radiation induced DNA damage (Dzikiewicz-Krawczyk_2012), cell cycle mediated DNA synthesis and chromosomal instability (Dzikiewicz-Krawczyk_2012, Nowak_2017). The most pronounced variant effect results in reduced double stranded repair (DSB) activity through loss of association with MDC1 (Yamamoto_2014). Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments ranging from benign/likely benign (n=2) to uncertain significance (n=11) using the same literature assessed in the scope of this evaluation. Based on the evidence outlined above, the variant was classified as benign. - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 12, 2014 | - - |
Aplastic anemia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2004 | - - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NBN p.Ile171Val variant was identified in 84 of 9038 proband chromosomes (frequency: 0.01) from individuals or families with acute lymphoblastic leukemia, lung cancer, breast and ovarian cancer, head and neck cancer, colorectal cancer, aplastic anemia and other hematological malignancies and was not identified in 220 control chromosomes from healthy individuals (Varon 2001, Kaluzna 2015, Desjardins 2009, Ziolkowska 2007, Nowak 2008, Bogdanova 2008, Kanka 2007). The variant was also identified in the following databases: ClinVar (1x pathogenic: OMIM 1x “risk factor”; 4x uncertain significance: GeneDx, Ambry Genetics, Emory Genetics, University of Chicago; 1x benign Invitae; 1x not provided ITMI), LOVD 3.0 (1x not classified), and the Zhejiang University database (5x probably pathogenic, 1x pathogenic). The variant was not identified in the COSMIC database. The variant was identified in control databases in 418 of 277070 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017); it was identified in the following populations: European (Non-Finnish) in 327 of 126600 chromosomes (frequency 0.003), European (Finnish) in 37 of 25785 chromosomes (frequency 0.001), East Asian in 27 of 18870 chromosomes (frequency 0.001), Other in 8 of 6458 chromosomes (frequency 0.001), Ashkenazi Jewish in 4 of 10148 chromosomes (frequency 0.0004), African in 6 of 24026 chromosomes (frequency 0.0002), Latino in 8 of 34404 chromosomes (frequency 0.0002), and South Asian in 1 of 30782 chromosomes (frequency 0.00003). A Japanese child with aplastic anemia has been found to be homozygous for this variant. Lymphoblastoid cell lines from this patient and her carrier father showed increased polyploidy. In addition, the homozygous patient had higher frequency of chromosomal structural aberrations than her heterozygous father and had an intermediate frequency of chromosomal structural aberrations compared to that of the patient and controls, suggesting that the variant may affect genomic integrity in hematopoietic cells (Shimada 2004). However the patient had no features of Nijmegen breakage syndrome. The p.Ile171Val residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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. - |
Acute lymphoid leukemia Uncertain:1
| Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Breast carcinoma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
NBN-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 27, 2023 | 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). - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Leukemia, acute lymphoblastic, susceptibility to Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Oct 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;T;T
Sift4G
Pathogenic
D;D;.;D
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at