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rs587776650

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_002485.5(NBN):c.657_661del(p.Lys219AsnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K219K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

NBN
NM_002485.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:38U:1O:4

Conservation

PhyloP100: 2.47
Variant links:
Genes affected
NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 8-89971213-ATTTGT-A is Pathogenic according to our data. Variant chr8-89971213-ATTTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 6940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89971213-ATTTGT-A is described in Lovd as [Pathogenic]. Variant chr8-89971213-ATTTGT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NBNNM_002485.5 linkuse as main transcriptc.657_661del p.Lys219AsnfsTer16 frameshift_variant 6/16 ENST00000265433.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.657_661del p.Lys219AsnfsTer16 frameshift_variant 6/161 NM_002485.5 P1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000191
AC:
48
AN:
250742
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135568
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000926
Gnomad NFE exome
AF:
0.000388
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000228
AC:
333
AN:
1460906
Hom.:
0
AF XY:
0.000239
AC XY:
174
AN XY:
726760
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000938
Gnomad4 NFE exome
AF:
0.000285
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000364
Hom.:
0
Bravo
AF:
0.000219
EpiCase
AF:
0.000600
EpiControl
AF:
0.000237

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:38Uncertain:1Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:18Other:1
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalSep 28, 2022The 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. This variant has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This is the most common pathogenic variant reported in individuals affected with Nijmegen breakage syndrome (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 (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 (https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 04, 2015- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterresearchMiami Human Genetics, University Of Miami Miller School Of MedicineNov 16, 2015- -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 15, 2008- -
Pathogenic, criteria provided, single submitterresearchDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDec 15, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaOct 12, 2018This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 08, 2019The 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. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 29, 2024This sequence change creates a premature translational stop signal (p.Lys219Asnfs*16) in the NBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 536 amino acid(s) of the NBN protein. This variant is present in population databases (rs587776650, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with NBN-related conditions (PMID: 14973119, 15185344, 18606567, 19908051, 24113799). It is commonly reported in individuals of Slavic ancestry (PMID: 9590180). This variant is also known as 657del5. ClinVar contains an entry for this variant (Variation ID: 6940). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NBN function (PMID: 16033915, 22131123, 22941933). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMay 05, 2023Criteria applied: PVS1,PS3,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). It is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006940 / PMID: 9590180). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedclinical testingClinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"May 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCounsylJun 13, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterApr 27, 2022PVS1, PS3, PM3 -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 25, 2015- -
not provided Pathogenic:6Other:1
risk factor, flagged submissionclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 08, 2019The 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. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 14, 2023The NBN c.657_661del; 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). However, more recent large, multi-ethnic case control studies have demonstrated that heterozygous pathogenic NBN variants are not associated with an increased risk for breast cancer (Breast Cancer Association Consortium 2021, Hu 2021). Data regarding other cancer risks remains inconclusive. 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. References: Breast Cancer Association Consortium, Dorling L, Carvalho S, et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021;384(5):428-439. PMID: 33471991 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. PMID: 19908051. 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. PMID: 24113799. Hu C et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med. 2021;384(5):440-451. PMID: 33471974 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. PMID: 19635536. 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. PMID: 11279524. 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. PMID: 15185344. 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. PMID: 9590180. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 11, 2021Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Case control studies suggest this variant is associated with prostate cancer; earlier studies also describe associated risk for breast cancer and lymphoma, though additional studies have not been supportive (Zhang 2012, Cybulski 2013, Gao 2013, Rogoa-Janiszewska 2020, Wokoorczyk 2020, Hu 2021); Also known as 657del5; This variant is associated with the following publications: (PMID: 9590180, 19908051, 23317186, 32255556, 18073374, 24619942, 26929905, 28649662, 29785153, 30426508, 30322717, 30612635, 22131123, 22293976, 25485873, 23765759, 16770759, 23149842, 22941933, 19635536, 14973119, 19452044, 16033915, 27150568, 27038244, 19393249, 27276934, 26083025, 26822949, 25980754, 27616075, 28008555, 26681312, 28374160, 28873162, 28376765, 25186627, 15185344, 11093281, 18606567, 11279524, 16544999, 11953735, 18940477, 12833396, 12505263, 12123493, 10852373, 10398434, 9620777, 29368341, 29915322, 29555771, 29753700, 28152038, 26265251, 31173646, 30590007, 31187634, 31159747, 29419426, 31980526, 33178177, 31589614, 32338768, 33488600, 32441320, 32843899, 24113799, 33077847, 32427313) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 18, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024NBN: PVS1, PS3, PM2, PM3, PS4:Moderate -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoAug 22, 2022This frameshift variant alters the translational reading frame of the NBN mRNA and causes the premature termination of NBN protein synthesis. Functional studies have shown that this variant results in two proteins, the N-terminal p26 fragment and the p70 fragment produced from an internal initiation codon at position p.221 that lacks the N-terminal portion (PMID: 11279524 (2001), 25485873 (2014)). Another study has shown that the variant caused increased chromosomal instability in homozygous cells (PMID: 22131123 (2012)). The frequency of this variant in the general population, 0.00041 (21/50678 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. The c.657_661del variant is the most common pathogenic variant found in individuals affected by Nijmegen breakage syndrome (NBS) (PMID: 9590180 (1998), 20301355 (2017)). In the published literature, previous studies showed an association to breast cancer (PMID: 12845677 (2003), 22491912 (2012), 23317186 (2012)), however, recent studies do not support this association (PMID: 34072463 (2021), 33471974 (2021), 33471991 (2021)). The variant is also reported to have an increased risk overall for cancer (PMID: 24113799 (2013), 15185344 (2004)), including pancreatic cancer (PMID: 27150568 (2016), 35309086 (2022)), prostate cancer (PMID: 14973119 (2004)), medulloblastoma (PMID: 19908051 (2010)), and relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (PMID: 29419426 (2018)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:5Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 13, 2021The 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 (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). This variant has also been observed, in the homozyous and compound heterozygous state, in patients with Nijmegen Breakage syndrome (Matsuura S et al. Nat Genet, 1998 Jun;19:179-81; Kleier S et al. Clin Genet, 2000 May;57:384-7; Szczauba 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. However, functional studies have indicated that this alteration may partially escape nonsense-mediated decay and produce a protein with some residual function (Maser RS et al. Nat Genet, 2001 Apr;27:417-21). Based on the supporting clinical evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 09, 2021This 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). -
Pathogenic, criteria provided, single submitterclinical testingUniversity of Washington Department of Laboratory Medicine, University of WashingtonNov 20, 2015- -
Uncertain significance, flagged submissionresearchDepartment of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf-- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMay 06, 2019- -
Pathogenic, criteria provided, single submittercurationSema4, Sema4May 28, 2021- -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMOct 15, 2008- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Molecular Diagnostics, Institute of Oncology LjubljanaApr 02, 2020- -
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria providedcase-control;clinical testingCZECANCA consortiumJun 11, 2019- -
Carcinoma of pancreas Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumMar 04, 2021- -
Lissencephaly;C4551563:Microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaOct 06, 2015- -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingMedical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health SciencesAug 20, 2021Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive -
NBN-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 03, 2023The NBN c.657_661del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys219Asnfs*16). The c.657_661del variant (also known as c.657del5) in the NBN gene is a founder pathogenic variant in the Slavic population and causes Nijmegen breakage syndrome in the homozygous state or in combination with another pathogenic variant in NBN (Varon et al. 1998. PubMed ID: 9590180). Functionally, it has been hypothesized to be a hypomorph, which results in a truncated protein with residual activity of the full-length NBN protein (Maser et al. 2001. PubMed ID: 11279524; Dzikiewicz-Krawczyk et al. 2011. PubMed ID: 22131123). However, this variant has been reported in up to ~0.04% of individuals (primarily within Europeans) in a large population database of presumably healthy individuals (http://gnomad.broadinstitute.org/variant/8-90983441-ATTTGT-A). In ClinVar, this variant has been classified as pathogenic as well as a risk factor (https://www.ncbi.nlm.nih.gov/clinvar/variation/6940/). Frameshift variants in NBN are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedcase-controlCZECANCA consortiumMay 17, 2022- -
Familial cancer of breast;C0398791:Microcephaly, normal intelligence and immunodeficiency Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776650; hg19: chr8-90983441; API