ClinVar Miner

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

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Total submissions: 34
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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 The c.657_661delACAAA pathogenic mutation, located in coding exon 6 of the NBN gene, results from a deletion of 5 nucleotides at positions 657 to 661, causing a translational frameshift with a predicted alternate stop codon (p.K219Nfs*16). The c.657_661delACAAA mutation (commonly referred to as 657del5 in the literature) is the most common NBN mutation in Eastern European individuals with Nijmegen Breakage Syndrome and is estimated to account for 90% of all mutant alleles in this population (Concannon P & Gatti R. Nijmegen Breakage Syndrome.1999 May17 [Updated 2011 Mar 1]. In: Pagon RA, Bird TD, Dolan CR, et al. editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1176/). One study showed a high frequency of heterozygotes for c.657_661delACAAA in three Slav populations, with a mean prevalence of 1/177. The highest heterozygote frequency, 1/154, was in the Czech population (Varon R et al. Eur. J. Hum. Genet. 2000 Nov;8:900-2). This mutation has been reported with increased frequency in individuals with medulloblastoma, prostate cancer, pancreatic cancer, melanoma, breast cancer, colon cancer, and non-Hodgkin's lymphoma (Borecka M et al. Gene. 2016 Aug;587:169-72; Ciara E et al. Acta Neuropathol. 2010 Mar;119:325-34; Cybulski C et al. Cancer Res. 2004 Feb;64:1215-9; Domagala P et al. PLoS ONE. 2015 Jun;10:e0130393; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Lhota F et al. Clin. Genet. 2016 Oct;90:324-33; Steffen J et al. Int. J. Cancer. 2004 Aug;111:67-71). A case study examined an individual who was homozygous for this mutation, who was found to have Nijmegen breakage syndrome with macrocephaly, schizencephaly and large CSF spaces (SzczaÅ‚uba K et al. J. Appl. Genet. 2012 May;53:189-91). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000007353 SCV000218835 pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-11-02 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 Health, Inc RCV000133576 SCV000292133 pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This variant deletes 5 nucleotides in exon 6 of the NBN gene, creating a frameshift and premature translation stop signal. This variant is also known as 657del5 in the literature. While cells homozygous for this variant express a truncated protein at low level (PMID: 11279524, 19635536), these cells are found to be defective in chromosome breakage assay (PMID: 22131123) and in DNA damage response (PMID: 22941933). This is a common variant found in individuals affected with autosomal recessive Nijmegen Breakage Syndrome, especially among individuals of eastern and central European origins and is a suspected founder mutation in the Slavic population (PMID: 9590180, 9620777). Multiple parent-child trios have demonstrated the recessive inheritance pattern of this variant for Nijmegen Breakage Syndrome (PMID: 9620777, 12123493, 16544999). Two meta-analyses of breast cancer case-control studies have reported that carriers have increased breast cancer risk (OR=2.60 and 2.66) (PMID: 23317186, 23765759). This variant also has been observed in individuals affected with breast, ovarian and pancreatic cancer (PMID: 12845677, 26083025, 26681312, 27150568, 27616075) and one individual each affected with leukemia, lymphoma (PMID: 12833396) and Lynch syndrome-associated cancer and/or colorectal polpys (PMID: 25980754). This variant has been identified in 57/282132 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of NBN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2021-01-09 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 none provided 2020-07-09 criteria provided, single submitter clinical testing The NBN c.657_661delACAAA; p.Lys219AsnfsTer16 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.Lys219AsnfsTer16 variant is considered to be pathogenic.
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 2021-06-01 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 RCV000007353 SCV001366157 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-10-12 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000133576 SCV001449031 pathogenic Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000007353 SCV001478131 pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-12-15 criteria provided, single submitter research
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000133576 SCV001482292 uncertain significance Hereditary cancer-predisposing syndrome criteria provided, single submitter research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000007354 SCV001499751 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000007353 SCV001737447 pathogenic Microcephaly, normal intelligence and immunodeficiency 2021-05-21 criteria provided, single submitter clinical testing The NBN c.657_661del (p.Lys219fs) change deletes five nucleotides and causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-90983441-ATTTGT-A?dataset=gnomad_r2_1). This is the most common pathogenic variant reported in individuals affected with Nijmegen breakage syndrome (PM3; PMID: 9590180, 20301355). In addition, this variant has been identified as heterozygous in individuals with many cancer types including breast, lymphoma, prostate, melanoma, medulloblastoma, and others (PS4; PMID: 15185344, 14973119, 18606567, 19908051, 24113799). Case-control studies have demonstrated evidence of association with breast cancer (OR = 2.63), prostate cancer (OR = 5.87), and lymphoma (OR = 2.93) (PMID: 23317186, 24113799). This variant is present 5x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM3, BS2_supporting.
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
CZECANCA consortium RCV001270991 SCV001451803 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided case-control
Natera, Inc. RCV000007353 SCV001460733 pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357671 SCV001553205 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Lys219Asnfs*16 variant was identified in 50 of 30494 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic ductal adenocarcinoma, medulloblastoma, prostate cancer, breast cancer, ovarian cancer, non-Hodgkin lymphoma, or colorectal cancer and was present in 20 of 6450 control chromosomes (frequency: 0.003) from healthy individuals (Borecka 2016, Ciara 2010, Cybulski 2004, Domagala 2015, Kraus 2017, Lhota 2016, Steffen 2004, Susswein 2015, Tung 2015). This variant is a Slavic founder mutation with carrier frequency among newborns in the range of 1/154 in the Czech Republic to 1/190 in Poland (Steffen 2004). The variant was also identified in dbSNP (ID: rs587776650 as "With Pathogenic allele"), ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and twelve other submitters), and LOVD 3.0 (4x). The variant was identified in control databases in 55 of 276598 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 50 of 126360 chromosomes (freq: 0.0004), Other in 1 of 6436 chromosomes (freq: 0.0002), Finnish in 2 of 25738 chromosomes (freq: 0.00008), and Latino in 2 of 34324 chromosomes (freq: 0.00006); it was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. Functional studies have reported that the variant leads to two truncated fragments, p26 and p70 nibrin, and the translation of a short N-terminal protein with FHA/BRCT domains, therefore maintaining some function of the full-length NBS1 protein (Dzikiewicz-Krawczyk 2008, Cilli 2014). The variant has been associated with an increased risk of breast cancer and medulloblastoma, and a significant increase in overall cancer risks (Zhang 2013, Ciara 2010, Gao 2013, Borecka 2016). The c.657_661del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 219 and leads to a premature stop codon at position 234. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the NBN gene are an established mechanism of disease in NBN-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium RCV001391203 SCV001593146 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535498 SCV001749450 not provided Familial cancer of breast; Microcephaly, normal intelligence and immunodeficiency no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 10-26-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001574072 SCV001797297 pathogenic Breast carcinoma 2021-08-20 no assertion criteria provided clinical testing Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive

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