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.
ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.657_661del (p.Lys219fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(47)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
47
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002485.5(NBN):c.657_661del (p.Lys219fs)
Variation ID: 6940 Accession: VCV000006940.98
- Type and length
-
Deletion, 5 bp
- Location
-
Cytogenetic: 8q21.3 8: 89971214-89971218 (GRCh38) [ NCBI UCSC ] 8: 90983442-90983446 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 5, 2015 Nov 24, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002485.5:c.657_661del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Lys219fs frameshift NM_002485.5:c.657_661delACAAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001024688.3:c.411_415del NP_001019859.1:p.Lys137fs frameshift NM_002485.4:c.657_661delACAAA NC_000008.11:g.89971217_89971221del NC_000008.10:g.90983445_90983449del NG_008860.1:g.18454_18458del LRG_158:g.18454_18458del - Protein change
- K137fs, K219fs
- Other names
-
657del5
p.Lys219Asnfs*16
- Canonical SPDI
- NC_000008.11:89971213:TTTGTTTT:TTT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NBN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3421 | 3594 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (21) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000007353.53 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Apr 2, 2020 | RCV000007354.13 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Aug 13, 2021 | RCV000133576.31 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000212733.61 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 6, 2015 | RCV000415248.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 4, 2021 | RCV001391203.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 11, 2019 | RCV001270991.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001357671.10 | |
| not provided (1) |
no classification provided
|
- | RCV001535498.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 20, 2021 | RCV001574072.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 17, 2022 | RCV002280859.8 | |
|
NBN-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 20, 2024 | RCV003389666.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 27, 2024 | RCV003460432.2 | |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Nijmegen breakage syndrome
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000248141.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Pathogenic
(Nov 16, 2015)
|
criteria provided, single submitter
Method: research
|
Microcephaly, normal intelligence and immunodeficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Miami Human Genetics, University Of Miami Miller School Of Medicine
Study: Miami Human Genetics
Accession: SCV000256868.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Clinical Features:
Microcephaly (present) , Abnormality of chromosome stability (present) , Intellectual disability (present)
|
|
|
Pathogenic
(Oct 06, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Lissencephaly
Microcephaly
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492771.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
|
Pathogenic
(Nov 25, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697978.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
|
|
|
Pathogenic
(May 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365920.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449031.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Oct 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366157.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
|
|
|
Pathogenic
(Jan 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821748.3
First in ClinVar: Oct 10, 2018 Last updated: Oct 02, 2021 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002045955.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Pathogenic
(May 28, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002536702.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NBN c.657_661del (p.Lys219Asnfs*16, also known as 657del5) variant has been associated with increased risk for NBN-related cancers. This variant has been observed in multiple … (more)
The NBN c.657_661del (p.Lys219Asnfs*16, also known as 657del5) variant has been associated with increased risk for NBN-related cancers. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (0.040%, the Genome Aggregation Database (gnomAD); PMID:32461654). This variant is also present in the ClinVar database (ID: 6940). Additionally, in the bi-allelic state, this variant is the most common variant associated with autosomal recessive Nijmegen Breakage Syndrome (NBS) (PMID:22373003). A meta-analysis has reported an increased risk of developing cancer in the Caucasian population (OR=2.79 [95% CI 2.17-3.68] PMID:24113799). The stratified analysis from this same study reported significant odds ratios in carriers of the variant for multiple cancers, particularly breast cancer (OR = 2.51 [95% CI=1.68-3.73]), prostate cancer (OR = 5.87 [95% CI=2.51-13.75]), and lymphoma (OR = 2.93 [95% CI=1.62-5.29]). Additionally, a case control study has reported an association between this variant and pancreatic ductal adenocarcinoma in Czechs of Slavic descent (OR = 9.7 [95% CI= 1.9-50.2] PMID:27150568). This variant is predicted to cause a frameshift at amino acid 219 that results in premature termination 16 amino acids downstream which is a candidate for nonsense-mediated decay (NMD) leading to absent protein (loss of function). However, it has been shown that the mRNA escapes NMD via reinitiating translation and results in an N-terminally truncated NBN protein that leads to a partially functional protein (PMID: 11279524). Additional in vitro functional studies support an impact on protein function (PMID:22131123) and loss of function of the NBN gene is an established disease mechanism in autosomal recessive NBS. In summary, this variant is not expected to cause highly penetrant Mendelian disease in the heterozygous form but is an established risk allele and is classified as pathogenic with low penetrance for the development of breast, prostate, and lymphoid cancers. (less)
|
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573068.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The 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 … (more)
The 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. (less)
Clinical Features:
Microcephaly (present) , Fetal growth restriction (present) , Ventricular septal defect (present) , Hydronephrosis (present) , Delayed speech and language development (present) , Growth delay … (more)
Microcephaly (present) , Fetal growth restriction (present) , Ventricular septal defect (present) , Hydronephrosis (present) , Delayed speech and language development (present) , Growth delay (present) (less)
|
|
|
Pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838310.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010433.3
First in ClinVar: Oct 30, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Aug 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889554.4
First in ClinVar: Sep 13, 2018 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the NBN mRNA and causes the premature termination of NBN protein synthesis. Functional studies have shown … (more)
This 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. (less)
|
|
|
Pathogenic
(Jun 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018221.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218835.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This 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, … (more)
This 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. (less)
|
|
|
Pathogenic
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199284.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266100.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 50-59 years
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
ovarian cancer (present) , endometrial cancer (present)
Age: 50-59 years
|
|
|
Pathogenic
(Jun 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000678042.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163582.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
|
Pathogenic
(Dec 15, 2020)
|
criteria provided, single submitter
Method: research
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: no
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478131.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499751.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Pathogenic
(Apr 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002568311.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
PVS1, PS3, PM3
|
|
|
Pathogenic
(Sep 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001737447.3
First in ClinVar: Jun 19, 2021 Last updated: Oct 22, 2022 |
Comment:
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 … (more)
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. 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. (less)
|
|
|
Pathogenic
(Nov 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149712.16
First in ClinVar: May 14, 2014 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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 … (more)
Frameshift 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) (less)
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Pathogenic
(May 05, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027783.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Criteria applied: PVS1,PS3,PS4,PM2_SUP
Clinical Features:
Family history of cancer (present)
Sex: male
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Pathogenic
(Nov 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160103.3
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The 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 … (more)
The 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. (less)
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Pathogenic
(Aug 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000183792.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
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, … (more)
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 (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. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Microcephaly, normal intelligence and immunodeficiency
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051878.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Mar 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Aplastic anemia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004199484.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Microcephaly, normal intelligence and immunodeficiency
Affected status: yes
Allele origin:
germline
|
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV005326336.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
The p.Lys219Asnfs*16 variant is predicted to substitute the lysine at amino acid position 219 with an asparagine followed by a premature termination codon after 16 … (more)
The p.Lys219Asnfs*16 variant is predicted to substitute the lysine at amino acid position 219 with an asparagine followed by a premature termination codon after 16 amino acids. This is predicted to result in decreased function of the NBN protein due to a truncated or absent gene product. The p.Lys219Asnfs*16 variant is a known founder variant among individuals of Slavic ancestry and has been reported many times in the homozygous state in affected individuals (PMID: 9590180, 11093281, 29419426 and others). The p.Lys219Asnfs*16 variant accounts for approximately 100% of pathogenic alleles in individuals from Poland, Czech Republic, and Ukraine and for 70% of pathogenic alleles in the United States. It is estimated that the carrier frequency of the p.Lys219Asnfs*16 variant is as high as 1 in 154 individuals of Slavic origin but varies by region (PMID: 11093281). (less)
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Pathogenic
(Aug 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245910.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
NBN: PVS1, PS3, PS4:Moderate
Number of individuals with the variant: 33
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Pathogenic
(Aug 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413859.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP4, PS3, PVS1
Number of individuals with the variant: 2
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Nijmegen breakage syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001460733.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Oct 15, 2008)
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no assertion criteria provided
Method: literature only
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NIJMEGEN BREAKAGE SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000027552.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 01, 2016 |
Comment on evidence:
In patients of Slavic origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 … (more)
In patients of Slavic origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 of the NBS1 gene (657del5), resulting in a frameshift and a truncated protein. A total of 46 patients homozygous for this mutation were identified. The mutation was found exclusively on a specific 'Slavic' haplotype of linked polymorphic markers. Matsuura et al. (1998) found the same 5-bp deletion in the NBS1 gene in 13 NBS patients of Slavic or German origin. Twelve patients were homozygous for the deletion and 1 was heterozygous. The deletion introduced a premature termination signal at codon 218, which was predicted to result in a severely truncated polypeptide. Matsuura et al. (1998) concluded that they had identified the gene involved in NBS because complementation was effected by a YAC that contained the gene and because no (or extremely reduced) expression of the gene was found in a patient without the deletion but with the NBS phenotype. The presence of a founder mutation in 13 of 14 cases, with no demonstration of the deletion in 50 normal individuals of the same ethnic origin or in 7 normal chromosomes from NBS parents, supported this conclusion. The truncating 657del5 had been identified in 90% of NBS patients. NBS shares a number of features with ataxia-telangiectasia (208900), the most notable being high sensitivity to ionizing radiation and predisposition to cancer. Patients who are heterozygous for the ATM mutation are predisposed to breast cancer. Since the NBS phenotype at the cellular level is very similar to that of ataxia-telangiectasia, Carlomagno et al. (1999) screened 477 German breast cancer patients, aged under 51 years, and 866 matched controls for the common NBS mutation. They identified 1 carrier among the cases and 1 among the controls, indicating that the population frequency of this NBS mutation is 1 in 866 persons (95% CI = 1 in 34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million persons. The proportion of breast cancer attributable to this mutation is less than 1%. Kleier et al. (2000) reported a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for ataxia-telangiectasia, that disorder was diagnosed. However, the diagnosis of NBS was suggested by the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and telangiectasia. DNA analysis demonstrated homozygosity for the major mutation in the NBS1 gene, 657del5. Maser et al. (2001) tested the hypothesis that the NBS1 657del5 mutation is a hypomorphic defect. They showed that NBS cells harboring the 657del5 mutation contained a predicted 26-kD N-terminal protein, NBS1(p26), and a 70-kD NBS1 protein, NBS1(p70), lacking the native N terminus. The 26-kD protein is not physically associated with the MRE11 complex (600814), whereas the 70-kD species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS mRNA using an open reading frame generated by the 657del5 frameshift. Maser et al. (2001) proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype. Tekin et al. (2002) reported a consanguineous Turkish family whose first son died of anal atresia and whose second son, the proband, presented with severe pre- and postnatal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosome instability, and rhabdomyosarcoma in the anal region. The patient was homozygous for the 657del5 mutation in the NBS1 gene, which is responsible for NBS in most Slavic populations. The family was the first diagnosed with NBS in the Turkish population and was one of the most severely affected examples of the syndrome. Drabek et al. (2002) presented PCR with sequence specific primers as a method for detection of the 657del5 mutation. They confirmed a high carrier frequency in the Czech population (1 in 106 persons; 95% CI = 1 in 331 to 1 in 46). In Russian children, Resnick et al. (2003) screened for the 657del5 NBS1 mutation in 548 controls and 68 patients with lymphoid malignancies. No carrier of the mutation was found in the control group. The mutation was found in heterozygous form in 2 of the 68 patients from the group of lymphoid malignancies, 1 with acute lymphoblastic leukemia (see 159555) and 1 with non-Hodgkin lymphoma (605027). Several relatives of the patient with non-Hodgkin lymphoma who carried the same mutation had cancer (acute lymphoblastic leukemia, breast cancer, gastrointestinal cancers), suggesting that heterozygosity may predispose to malignant disorders. In monozygotic twin brothers with a severe form of NBS without chromosomal instability, Seemanova et al. (2006) identified compound heterozygosity for the 657del5 mutation and a 643C-T transition in exon 6 of the NBS1 gene, resulting in an arg215-to-trp (R215W) substitution (602667.0009). Both infants showed reduced expression of full-length nibrin, and radiation response processes were strongly reduced in their cells. Their mother and father were heterozygous for the 657del5 mutation and the R215W mutation, respectively, as were their respective grandfathers. In a 3-month-old boy with NBS, Varon et al. (2007) identified homozygosity for the 657del5 mutation; the patient's mother carried the mutation, whereas his father was homozygous for the wildtype allele. Analysis of 27 microsatellite markers covering all of chromosome 8 revealed that the patient had a homozygous haplotype for all of the markers, whereas the mother carried the same haplotype in heterozygous state. The authors stated that this was the first patient with NBS due to maternal isodisomy of chromosome 8. Porhanova et al. (2008) reported a 52-year-old Russian woman with ovarian cancer (see 604370) who was found to be compound heterozygous for a mutation in the BRCA1 gene (113705.0018) and the common Slavic 657del5 mutation in the NBN gene. Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. Porhanova et al. (2008) commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes. (less)
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risk factor
(Oct 15, 2008)
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no assertion criteria provided
Method: literature only
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OVARIAN CANCER, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000027553.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016 |
Comment on evidence:
In patients of Slavic origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 … (more)
In patients of Slavic origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 of the NBS1 gene (657del5), resulting in a frameshift and a truncated protein. A total of 46 patients homozygous for this mutation were identified. The mutation was found exclusively on a specific 'Slavic' haplotype of linked polymorphic markers. Matsuura et al. (1998) found the same 5-bp deletion in the NBS1 gene in 13 NBS patients of Slavic or German origin. Twelve patients were homozygous for the deletion and 1 was heterozygous. The deletion introduced a premature termination signal at codon 218, which was predicted to result in a severely truncated polypeptide. Matsuura et al. (1998) concluded that they had identified the gene involved in NBS because complementation was effected by a YAC that contained the gene and because no (or extremely reduced) expression of the gene was found in a patient without the deletion but with the NBS phenotype. The presence of a founder mutation in 13 of 14 cases, with no demonstration of the deletion in 50 normal individuals of the same ethnic origin or in 7 normal chromosomes from NBS parents, supported this conclusion. The truncating 657del5 had been identified in 90% of NBS patients. NBS shares a number of features with ataxia-telangiectasia (208900), the most notable being high sensitivity to ionizing radiation and predisposition to cancer. Patients who are heterozygous for the ATM mutation are predisposed to breast cancer. Since the NBS phenotype at the cellular level is very similar to that of ataxia-telangiectasia, Carlomagno et al. (1999) screened 477 German breast cancer patients, aged under 51 years, and 866 matched controls for the common NBS mutation. They identified 1 carrier among the cases and 1 among the controls, indicating that the population frequency of this NBS mutation is 1 in 866 persons (95% CI = 1 in 34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million persons. The proportion of breast cancer attributable to this mutation is less than 1%. Kleier et al. (2000) reported a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for ataxia-telangiectasia, that disorder was diagnosed. However, the diagnosis of NBS was suggested by the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and telangiectasia. DNA analysis demonstrated homozygosity for the major mutation in the NBS1 gene, 657del5. Maser et al. (2001) tested the hypothesis that the NBS1 657del5 mutation is a hypomorphic defect. They showed that NBS cells harboring the 657del5 mutation contained a predicted 26-kD N-terminal protein, NBS1(p26), and a 70-kD NBS1 protein, NBS1(p70), lacking the native N terminus. The 26-kD protein is not physically associated with the MRE11 complex (600814), whereas the 70-kD species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS mRNA using an open reading frame generated by the 657del5 frameshift. Maser et al. (2001) proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype. Tekin et al. (2002) reported a consanguineous Turkish family whose first son died of anal atresia and whose second son, the proband, presented with severe pre- and postnatal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosome instability, and rhabdomyosarcoma in the anal region. The patient was homozygous for the 657del5 mutation in the NBS1 gene, which is responsible for NBS in most Slavic populations. The family was the first diagnosed with NBS in the Turkish population and was one of the most severely affected examples of the syndrome. Drabek et al. (2002) presented PCR with sequence specific primers as a method for detection of the 657del5 mutation. They confirmed a high carrier frequency in the Czech population (1 in 106 persons; 95% CI = 1 in 331 to 1 in 46). In Russian children, Resnick et al. (2003) screened for the 657del5 NBS1 mutation in 548 controls and 68 patients with lymphoid malignancies. No carrier of the mutation was found in the control group. The mutation was found in heterozygous form in 2 of the 68 patients from the group of lymphoid malignancies, 1 with acute lymphoblastic leukemia (see 159555) and 1 with non-Hodgkin lymphoma (605027). Several relatives of the patient with non-Hodgkin lymphoma who carried the same mutation had cancer (acute lymphoblastic leukemia, breast cancer, gastrointestinal cancers), suggesting that heterozygosity may predispose to malignant disorders. In monozygotic twin brothers with a severe form of NBS without chromosomal instability, Seemanova et al. (2006) identified compound heterozygosity for the 657del5 mutation and a 643C-T transition in exon 6 of the NBS1 gene, resulting in an arg215-to-trp (R215W) substitution (602667.0009). Both infants showed reduced expression of full-length nibrin, and radiation response processes were strongly reduced in their cells. Their mother and father were heterozygous for the 657del5 mutation and the R215W mutation, respectively, as were their respective grandfathers. In a 3-month-old boy with NBS, Varon et al. (2007) identified homozygosity for the 657del5 mutation; the patient's mother carried the mutation, whereas his father was homozygous for the wildtype allele. Analysis of 27 microsatellite markers covering all of chromosome 8 revealed that the patient had a homozygous haplotype for all of the markers, whereas the mother carried the same haplotype in heterozygous state. The authors stated that this was the first patient with NBS due to maternal isodisomy of chromosome 8. Porhanova et al. (2008) reported a 52-year-old Russian woman with ovarian cancer (see 604370) who was found to be compound heterozygous for a mutation in the BRCA1 gene (113705.0018) and the common Slavic 657del5 mutation in the NBN gene. Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. Porhanova et al. (2008) commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes. (less)
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Pathogenic
(Jun 20, 2024)
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no assertion criteria provided
Method: clinical testing
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NBN-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000806448.3
First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024 |
Comment:
The 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 … (more)
The 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 is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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. (less)
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Pathogenic
(Jun 11, 2019)
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no assertion criteria provided
Method: case-control, clinical testing
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Breast and/or ovarian cancer
Affected status: no, yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001451803.1
First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
Observation 2:
Number of individuals with the variant: 12
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553205.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Mar 04, 2021)
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no assertion criteria provided
Method: clinical testing
|
Carcinoma of pancreas
Affected status: yes
Allele origin:
germline
|
CZECANCA consortium
Accession: SCV001593146.1
First in ClinVar: May 14, 2021 Last updated: May 14, 2021 |
Number of individuals with the variant: 3
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(Aug 20, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001797297.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Age: 60-69 years
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Likely pathogenic
(May 17, 2022)
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no assertion criteria provided
Method: case-control
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Hepatocellular carcinoma
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV002569170.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
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Pathogenic
(May 01, 2022)
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no assertion criteria provided
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: yes
Allele origin:
germline
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Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Accession: SCV002573431.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000494627.2
First in ClinVar: Jul 01, 2016 Last updated: Oct 01, 2022 |
Ethnicity/Population group: Slavic
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not provided
(-)
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no classification provided
Method: phenotyping only
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Microcephaly, normal intelligence and immunodeficiency
Familial cancer of breast
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749450.2
First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormality of the liver (present) , Abnormality of the pancreas (present) , Abnormal delivery (present)
Indication for testing: Presymptomatic
Age: 30-39 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-10-26
Testing laboratory interpretation: Pathogenic
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risk factor
(May 08, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV001365763 appears to be redundant with SCV001365920.
(less)
Notes: SCV001365763 appears to
(...more)
Source: NCBI
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not provided
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365763.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Uncertain significance
(-)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
maternal
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Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
Accession: SCV001482292.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Family history: no
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Comment:
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).
Comment:
The 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.
Comment:
This 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.
Comment:
This 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.
Comment:
PVS1, PS3, PM3
Comment:
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. 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.
Comment:
Frameshift 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)
Comment:
Criteria applied: PVS1,PS3,PS4,PM2_SUP
Comment:
The 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.
Comment:
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 (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.
Comment:
The p.Lys219Asnfs*16 variant is predicted to substitute the lysine at amino acid position 219 with an asparagine followed by a premature termination codon after 16 amino acids. This is predicted to result in decreased function of the NBN protein due to a truncated or absent gene product. The p.Lys219Asnfs*16 variant is a known founder variant among individuals of Slavic ancestry and has been reported many times in the homozygous state in affected individuals (PMID: 9590180, 11093281, 29419426 and others). The p.Lys219Asnfs*16 variant accounts for approximately 100% of pathogenic alleles in individuals from Poland, Czech Republic, and Ukraine and for 70% of pathogenic alleles in the United States. It is estimated that the carrier frequency of the p.Lys219Asnfs*16 variant is as high as 1 in 154 individuals of Slavic origin but varies by region (PMID: 11093281).
Comment:
NBN: PVS1, PS3, PS4:Moderate
Comment:
PP4, PS3, PVS1
Comment:
The 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 is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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.
Comment:
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.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Comment:
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).
Comment:
The 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.
Comment:
This 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.
Comment:
This 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.
Comment:
PVS1, PS3, PM3
Comment:
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. 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.
Comment:
Frameshift 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)
Comment:
Criteria applied: PVS1,PS3,PS4,PM2_SUP
Comment:
The 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.
Comment:
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 (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.
Comment:
The p.Lys219Asnfs*16 variant is predicted to substitute the lysine at amino acid position 219 with an asparagine followed by a premature termination codon after 16 amino acids. This is predicted to result in decreased function of the NBN protein due to a truncated or absent gene product. The p.Lys219Asnfs*16 variant is a known founder variant among individuals of Slavic ancestry and has been reported many times in the homozygous state in affected individuals (PMID: 9590180, 11093281, 29419426 and others). The p.Lys219Asnfs*16 variant accounts for approximately 100% of pathogenic alleles in individuals from Poland, Czech Republic, and Ukraine and for 70% of pathogenic alleles in the United States. It is estimated that the carrier frequency of the p.Lys219Asnfs*16 variant is as high as 1 in 154 individuals of Slavic origin but varies by region (PMID: 11093281).
Comment:
NBN: PVS1, PS3, PS4:Moderate
Comment:
PP4, PS3, PVS1
Comment:
The 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 is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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.
Comment:
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.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Nijmegen Breakage Syndrome. | Adam MP | - | 2023 | PMID: 20301355 |
| Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes. | Emelyanova M | Therapeutic advances in medical oncology | 2022 | PMID: 35309086 |
| Bilateral Ovarian Germ Cell Tumor in a 46,XX Female with Nijmegen Breakage Syndrome and Hypergonadotropic Hypogonadism. | Krawczyk MA | Journal of clinical research in pediatric endocrinology | 2022 | PMID: 34544220 |
| Study of the Genetic Variants in BRCA1/2 and Non-BRCA Genes in a Population-Based Cohort of 2155 Breast/Ovary Cancer Patients, Including 443 Triple-Negative Breast Cancer Patients, in Argentina. | Solano AR | Cancers | 2021 | PMID: 34072659 |
| Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next? | Zuntini R | International journal of molecular sciences | 2021 | PMID: 34072463 |
| Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer. | Wagener R | European journal of human genetics : EJHG | 2021 | PMID: 33840814 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| A Population-Based Study of Genes Previously Implicated in Breast Cancer. | Hu C | The New England journal of medicine | 2021 | PMID: 33471974 |
| Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes. | Stolarova L | Biomedicines | 2020 | PMID: 33050356 |
| The spectrum of mutations predisposing to familial breast cancer in Poland. | Cybulski C | International journal of cancer | 2019 | PMID: 31173646 |
| The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. | Schubert S | International journal of cancer | 2019 | PMID: 30426508 |
| Heterozygous carriers of germline c.657_661del5 founder mutation in NBN gene are at risk of central nervous system relapse of B-cell precursor acute lymphoblastic leukemia. | Tomasik B | Haematologica | 2018 | PMID: 29419426 |
| Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. | Isaacsson Velho P | The Prostate | 2018 | PMID: 29368341 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
| The c.657del5 variant in the NBN gene predisposes to pancreatic cancer. | Borecka M | Gene | 2016 | PMID: 27150568 |
| Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients. | Lhota F | Clinical genetics | 2016 | PMID: 26822949 |
| Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers. | Domagala P | PloS one | 2015 | PMID: 26083025 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| Identification of the interactors of human nibrin (NBN) and of its 26 kDa and 70 kDa fragments arising from the NBN 657del5 founder mutation. | Cilli D | PloS one | 2014 | PMID: 25485873 |
| Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. | Gao P | Mutagenesis | 2013 | PMID: 24113799 |
| Current evidence on the relationship between two polymorphisms in the NBS1 gene and breast cancer risk: a meta-analysis. | Zhang ZH | Asian Pacific journal of cancer prevention : APJCP | 2012 | PMID: 23317186 |
| Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. | Mendez G | IUBMB life | 2012 | PMID: 22941933 |
| Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women. | Mateju M | Breast cancer research and treatment | 2012 | PMID: 22491912 |
| Nijmegen breakage syndrome (NBS). | Chrzanowska KH | Orphanet journal of rare diseases | 2012 | PMID: 22373003 |
| Nijmegen breakage syndrome with macrocephaly, schizencephaly and large CSF spaces—extended spectrum of the condition. | Szczałuba K | Journal of applied genetics | 2012 | PMID: 22293976 |
| Impact of heterozygous c.657-661del, p.I171V and p.R215W mutations in NBN on nibrin functions. | Dzikiewicz-Krawczyk A | Mutagenesis | 2012 | PMID: 22131123 |
| High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study. | Chrzanowska KH | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20444919 |
| Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. | Ciara E | Acta neuropathologica | 2010 | PMID: 19908051 |
| Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. | Lins S | Gene | 2009 | PMID: 19635536 |
| Ovarian cancer patient with germline mutations in both BRCA1 and NBN genes. | Porhanova NV | Cancer genetics and cytogenetics | 2008 | PMID: 18940477 |
| The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. | Dzikiewicz-Krawczyk A | Mutation research | 2008 | PMID: 18606567 |
| Nijmegen breakage syndrome (NBS) due to maternal isodisomy of chromosome 8. | Varon R | American journal of medical genetics. Part A | 2007 | PMID: 17103455 |
| Screening of Nijmegen breakage syndrome 1 mutations in four unrelated families by polymerase chain reaction using sequence-specific primers. | Di Masi A | Genetic testing | 2006 | PMID: 16544999 |
| Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. | Seemanová E | Journal of medical genetics | 2006 | PMID: 16033915 |
| Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. | Digweed M | DNA repair | 2004 | PMID: 15279809 |
| Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. | Steffen J | International journal of cancer | 2004 | PMID: 15185344 |
| NBS1 is a prostate cancer susceptibility gene. | Cybulski C | Cancer research | 2004 | PMID: 14973119 |
| Germline 657del5 mutation in the NBS1 gene in breast cancer patients. | Górski B | International journal of cancer | 2003 | PMID: 12845677 |
| 657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls. | Resnick IB | American journal of medical genetics. Part A | 2003 | PMID: 12833396 |
| Frequency of 657del(5) mutation of the NBS1 gene in the Czech population by polymerase chain reaction with sequence specific primers. | Drábek J | Cancer genetics and cytogenetics | 2002 | PMID: 12505263 |
| 657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family. | Tekin M | Clinical genetics | 2002 | PMID: 12123493 |
| Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. | Resnick IB | The Journal of pediatrics | 2002 | PMID: 11953735 |
| An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. | Maser RS | Nature genetics | 2001 | PMID: 11279524 |
| Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. | Varon R | European journal of human genetics : EJHG | 2000 | PMID: 11093281 |
| Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome. | Kleier S | Clinical genetics | 2000 | PMID: 10852373 |
| No evidence for a major role of heterozygous deletion 657del5 within the NBS1 gene in the pathogenesis of non-Hodgkin's lymphoma of childhood and adolescence. | Stanulla M | British journal of haematology | 2000 | PMID: 10848790 |
| Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. | The I | Archives of disease in childhood | 2000 | PMID: 10799436 |
| Determination of the frequency of the common 657Del5 Nijmegen breakage syndrome mutation in the German population: no association with risk of breast cancer. | Carlomagno F | Genes, chromosomes & cancer | 1999 | PMID: 10398434 |
| Positional cloning of the gene for Nijmegen breakage syndrome. | Matsuura S | Nature genetics | 1998 | PMID: 9620777 |
| The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. | Carney JP | Cell | 1998 | PMID: 9590181 |
| Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. | Varon R | Cell | 1998 | PMID: 9590180 |
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Text-mined citations for rs587776650 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.