ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.657_661del (p.Lys219fs) (rs587776650)

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 RCV000212733 SCV000149712 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing The NBN c.657_661delACAAA deletion causes a frameshift, which changes a Lysine to an Asparagine at codon 219, and creates a premature stop codon at position 16 of the new reading frame. NBN 657del5 has been described as a pathogenic founder variant of Slavic and Eastern European origin and is the most common pathogenic variant in patients with the related autosomal recessive condition called Nijmegen Breakage syndrome (Varon 1998). An in vitro study conducted by Lins et al. (2009) found that there was some selective loss of the mutant allele associated with this deletion, but much less than would be expected for mRNA eliminated by nonsense-mediated decay (NMD). In addition, RT-PCR analysis revealed no significant difference in NMD rate between the mutant and wild-type mRNA, suggesting that NMD is not the mechanism by which this variant exerts its effect (Lins 2009). This variable mRNA expression and degradation may explain the range of cancer risks that have been observed in association with this pathogenic variant.
Ambry Genetics RCV000133576 SCV000183792 pathogenic Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000007353 SCV000218835 pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-01-06 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 6 of the NBN mRNA (c.657_661delACAAA), causing a frameshift at codon 219. This creates a premature translational stop signal and would generally be expected to result in an absent or disrupted protein product. However, experimental studies have shown that this deletion introduces two in-frame start codons downstream of the frameshift, which can initiate protein translation and generate two truncated NBN proteins of similar length that maintain partial functionality (PMID: 11279524). This variant is present in population databases (rs587776650, ExAC 0.03%). This is the most common variant reported in individuals affected with Nijmegen breakage syndrome, and is considered to be a founder mutation in the Slavic population (PMID: 9590180). It is also known as 657del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 6940). Heterozygous carriers may have increased risk for several types of cancers including breast, lymphoma, prostate, melanoma, medulloblastoma and others (PMID: 15185344, 14973119, 18606567, 19908051, 24113799). In a large meta-analysis involving 15,184 cases and 54,081 controls from 21 studies, this variant was found to increase overall cancer risk in heterozygous carriers by close to three-fold (PMID: 24113799). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory,University of Chicago RCV000007353 SCV000248141 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-03-04 criteria provided, single submitter clinical testing
Miami Human Genetics,University of Miami Miller School of Medicine RCV000007353 SCV000256868 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-11-16 criteria provided, single submitter research
University of Washington Department of Laboratory Medicine, University of Washington RCV000133576 SCV000266100 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000133576 SCV000292133 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415248 SCV000492771 pathogenic Lissencephaly; Microcephaly 2015-10-06 criteria provided, single submitter clinical testing
Counsyl RCV000007353 SCV000678042 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-06-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000007353 SCV000697978 pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-11-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212733 SCV000806448 pathogenic not provided 2017-02-20 criteria provided, single submitter clinical testing
GeneKor MSA RCV000133576 SCV000821748 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This is a deletion of five base pairs from exon 6 of the NBN mRNA (c.657_661delACAAA), which results in frameshift after codon 219 and creation of a novel stop codon 16 amino acid residues later and would generally be expected to result in an absent or disrupted protein product.This is the most common variant reported in individuals affected with Nijmegen breakage syndrome (NBS), and is considered to be a founder mutation in the Slavic population (PMID: 9590180). It is also known as 657del5 in the literature. Heterozygous carriers may have increased risk for several types of cancers including breast, lymphoma, melanoma, medulloblastoma, prostate and others (PMID: 15185344, 14973119, 18606567, 19908051, 24113799). Experimental studies propose that this deletion encodes a partially functional protein that diminishes the severity of the NBS phenotype (PMID: 11279524). The mutation database Clinvar contains entries for this variant (Variation ID:6940).
Mendelics RCV000007353 SCV000838310 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212733 SCV000889554 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002228 SCV001160103 pathogenic not specified 2018-11-20 criteria provided, single submitter clinical testing The NBN c.657_661delACAAA; p.Lys219fs variant (rs587776650), also known as 657del5, is reported in the literature as the most common pathogenic variant and a founder mutation in the Slavic population in individuals affected with Nijmegen breakage syndrome (Varon 1998). Heterozygous carriers are also reported to have an increased risk for various cancers, including breast cancer, prostate cancer, colorectal cancer, lymphoma, melanoma, and medulloblastoma (Ciara 2010, Gao 2013, Steffen 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6940), and is found in the non-Finnish European population with an allele frequency of 0.040% (52/128,774 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. However, functional studies show two in-frame start codons created by the frameshift that can generate truncated NBN proteins with partial functionality (Lins 2009, Maser 2001). Based on available information, the p.Lys219fs variant is considered to be pathogenic. References: Ciara E et al. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 2010 Mar;119(3):325-34. 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. Lins S et al. Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. Gene. 2009 Nov 1;447(1):12-7. Maser RS et al. An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nat Genet. 2001 Apr;27(4):417-21. Steffen J et al. Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer. 2004 Aug 10;111(1):67-71. Varon R et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998 May 1;93(3):467-76.
Baylor Genetics RCV000007353 SCV001163582 pathogenic Microcephaly, normal intelligence and immunodeficiency criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212733 SCV001245910 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212733 SCV001365763 risk factor not provided 2019-05-08 criteria provided, single submitter clinical testing The p.Lys219AsnfsX16 variant in NBN is associated with an increased risk for NBN-related cancers (Gao 2013, Zhang 2012). Large meta-analyses have reported significant odds ratios in carriers of the variant for multiple cancers, particularly breast cancer (OR = 2.63 [95% CI=1.76-3.93]), prostate cancer (OR = 5.87 [95% CI=2.51-13.75]), and lymphoma (OR = 2.93 [95% CI=1.62-5.29]) (Gao 2013, Zhang 2012). Additionally, in the bi-allelic state, this variant is the most common variant associated with autosomal recessive Nijmegen Breakage Syndrome (NBS). It has also been identified in 52/128774 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID: 6940). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 219 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NBN gene is an established disease mechanism in autosomal recessive NBS. In vitro functional studies support an impact on protein function and show that this variant leads to the production of an abnormal protein product (Maser 2001, Dzikiewicz-Krawczyk 2012). In summary, this variant meets criteria to be classified as an established risk allele for breast, prostate, and lymphoid cancers.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000007353 SCV001365920 pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-05-08 criteria provided, single submitter clinical testing The p.Lys219AsnfsX16 variant in NBN is the most common NBN variant associated with autosomal recessive Nijmegen Breakage Syndrome (NBS) and has been reported as a founder variant in Slavic populations (Varon 1998). Additionally, in the heterozygous state, this variant has been found to increase risk to certain NBS-related cancers (Gao 2013, Zhang 2012). It has also been identified in 52/128774 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 6940). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 219 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NBN gene is an established disease mechanism in autosomal recessive NBS. In vitro functional studies support an impact on protein function and show that this variant leads to the production of an abnormal protein product (Maser 2001, Dzikiewicz-Krawczyk 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive NBS. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PS3_Supporting.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195737 SCV001366157 pathogenic Global developmental delay; Protruding ear; Microcephaly 2019-03-06 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196778 SCV001367411 pathogenic Seizures; Encephalopathy 2018-10-12 criteria provided, single submitter clinical testing This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. This variant was detected in heterozygous state.
OMIM RCV000007353 SCV000027552 pathogenic Microcephaly, normal intelligence and immunodeficiency 2008-10-15 no assertion criteria provided literature only
OMIM RCV000007354 SCV000027553 risk factor Breast-ovarian cancer, familial 1 2008-10-15 no assertion criteria provided literature only
GeneReviews RCV000007353 SCV000494627 pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-02-02 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785438 SCV000924010 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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.