ClinVar Miner

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

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121618 SCV000149706 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing This variant is denoted NBN c.511A>G at the cDNA level, p.Ile171Val (I171V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant, which is common in certain Slavic and Asian populations, has been reported as a possible risk factor for overall cancer risk as well as specific cancers, including medulloblastoma, lymphoma, leukemia, lung, and others (Ziolkowska 2007, Grajkowska 2009, Ciara 2010, Gao 2013, Mosor 2013, Kaluzna 2015, Sykorova 2015). Gao et al. (2013) proposed that NBN Ile171Val could be a low penetrance risk factor for certain types of cancer. Some studies observed an association with breast cancer (Roznowski 2008, Yamamoto 2014, Domagala 2015), but others did not come to the same conclusion (Kanka 2007, Bogdanova 2008, Zhang 2012, Gao 2013, Kim 2015). While NBN pathogenic variants typically cause the recessive disease Nijmegen breakage syndrome (NBS), a case report describes an 11 year old Japanese girl who was found to be homozygous for this variant and did not have NBS, though she did have aplastic anemia (Shimada 2004). Results from functional studies have been inconsistent; one in vitro study demonstrated similar behavior to wild type with respect to damage after irradiation (Dzikiewicz-Krawczyk 2012), while another demonstrated impaired homologous recombination, aberrant localization, and chromosomal instability (Yamamoto 2014). NBN Ile171Val was observed with allele frequencies of 0.6% (5/826) in the Japanese population (Shimada 2004) and 0.2% (14/8600) in European Americans in the NHLBI Exome Sequencing Project. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. NBN Ile171Val occurs at a position that is conserved across species and is located in the BRCT domain as well as the region mediating interaction with SP100 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. In summary, while the data are inconsistent with respect to breast cancer risk, this variant may be a risk factor for other types of cancer. Furthermore, the variant in a recessive form might cause diseases other than typical Nijmegen breakage syndrome. At this point, it is unclear whether NBN Ile171Val is a benign variant or a low penetrance pathogenic variant. We consider it to be a variant of uncertain significance.
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);Subpopulation frequency in support of benign classification;Structural Evidence;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
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 2019-12-31 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 RCV000121618 SCV000601696 uncertain significance not specified 2017-02-18 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
Integrated Genetics/Laboratory Corporation of America 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 2018-07-01 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 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.
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

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