ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.511A>G (p.Ile171Val) (rs61754966)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 25
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589577 SCV000149706 likely benign not provided 2021-06-03 criteria provided, single submitter clinical testing 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)
Ambry Genetics RCV000115797 SCV000186698 likely benign Hereditary cancer-predisposing syndrome 2019-03-24 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Structural Evidence;Subpopulation frequency in support of benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589577 SCV000231035 uncertain significance not provided 2015-03-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121618 SCV000248139 uncertain significance not specified 2014-12-12 criteria provided, single submitter clinical testing
Invitae RCV000197512 SCV000252775 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-04 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490266 SCV000267415 uncertain significance Acute lymphoid leukemia 2016-03-18 criteria provided, single submitter reference population
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589577 SCV000601696 uncertain significance not provided 2020-08-20 criteria provided, single submitter clinical testing
GeneID Lab - Advanced Molecular Diagnostics RCV000115797 SCV000680449 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121618 SCV000697972 benign not specified 2019-04-10 criteria provided, single submitter clinical testing 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589577 SCV000780919 uncertain significance not provided 2020-09-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589577 SCV000806444 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115797 SCV000822086 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000197512 SCV000838314 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589577 SCV000885817 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing 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.
Color Health, Inc RCV000115797 SCV000910544 benign Hereditary cancer-predisposing syndrome 2015-11-09 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030566 SCV001193656 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000197512 SCV001323249 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-04-27 criteria provided, single submitter clinical testing 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262350 SCV001440178 uncertain significance Breast carcinoma 2019-01-01 criteria provided, single submitter clinical testing
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000115797 SCV001482298 uncertain significance Hereditary cancer-predisposing syndrome criteria provided, single submitter research
Nilou-Genome Lab RCV000197512 SCV001737182 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000007360 SCV000027559 pathogenic Aplastic anemia 2004-10-01 no assertion criteria provided literature only
OMIM RCV000007361 SCV000027560 risk factor Leukemia, acute lymphoblastic, susceptibility to 2004-10-01 no assertion criteria provided literature only
ITMI RCV000121618 SCV000085816 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000197512 SCV001466980 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-04-03 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358233 SCV001553907 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.