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

gnomAD frequency: 0.00145  dbSNP: rs61754966

Total submissions: 29

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	2022-01-24	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197512	SCV000252775	benign	Microcephaly, normal intelligence and immunodeficiency	2024-02-01	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	likely benign	not provided	2023-06-27	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 Center for Human Genetics Tuebingen	RCV000589577	SCV000780919	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NBN: BP4, BS1:Supporting
GeneKor MSA	RCV000115797	SCV000822086	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492288	SCV000838314	likely benign	Hereditary cancer	2024-01-23	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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030566	SCV001193656	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, 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
Genome-Nilou Lab	RCV000197512	SCV001737182	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-05-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589577	SCV002010436	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115797	SCV002536691	likely benign	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000589577	SCV003813484	uncertain significance	not provided	2021-02-09	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004776268	SCV005382090	uncertain significance	Diffuse midline glioma, H3 K27-altered		criteria provided, single submitter	research
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004776269	SCV005382093	uncertain significance	Pediatric high-grade glioma		criteria provided, single submitter	research
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
PreventionGenetics, part of Exact Sciences	RCV003891430	SCV000806444	likely benign	NBN-related disorder	2023-04-27	no assertion criteria provided	clinical testing	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).
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.