ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.1142del (p.Pro381fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002485.5(NBN):c.1142del (p.Pro381fs)
Variation ID: 141731 Accession: VCV000141731.51
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 89955538 (GRCh38) [ NCBI UCSC ] 8: 90967766 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 1, 2016 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002485.5:c.1142del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Pro381fs frameshift NM_001024688.3:c.896del NP_001019859.1:p.Pro299fs frameshift NM_002485.4:c.1142delC NC_000008.11:g.89955539del NC_000008.10:g.90967767del NG_008860.1:g.34134del LRG_158:g.34134del - Protein change
- P299fs
- Other names
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- Canonical SPDI
- NC_000008.11:89955537:GG:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NBN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3381 | 3553 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000007358.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2021 | RCV000130355.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2023 | RCV000220768.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV003467143.1 |
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
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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
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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
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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. |
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279248.12
First in ClinVar: May 29, 2016 Last updated: Dec 31, 2022 |
Comment:
Observed with a pathogenic founder variant in individuals with Nijmegen breakage syndrome in published literature, but it is not known whether the variants occurred on … (more)
Observed with a pathogenic founder variant in individuals with Nijmegen breakage syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Varon et al., 1998; Bakhshi et al., 2003); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27038244, 22006311, 10799436, 24549055, 18593981, 26315354, 26270727, 15578693, 16033915, 10792024, 24072268, 28152038, 30322717, 30612635, 26689913, 33439686, 31589614, 29625052, 12621246, 9590180, 28888541, 29922827, 33804961, 36003761) (less)
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Pathogenic
(Oct 31, 2023)
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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: SCV004199485.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000609313.26
First in ClinVar: Oct 30, 2017 Last updated: May 12, 2024 |
Comment:
NBN: PVS1, PM2
Number of individuals with the variant: 3
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Likely pathogenic
(May 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000678049.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(Jan 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001337953.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: NBN c.1142delC (p.Pro381GlnfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NBN c.1142delC (p.Pro381GlnfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.4e-05 in 249986 control chromosomes (gnomAD). c.1142delC has been reported in the literature in multiple individuals affected with Nijmegen Breakage Syndrome (e.g. Bakshi_2003, Varon_1998) as well as in breast and/or ovarian cancer patients (Ramus_2015, Walsh_2011, Carter_2018). These data indicate that the variant is very likely to be associated with disease. No Nibrin protein expression was detected in a cell line derived from a compound heterozygous patient who harbored this variant and another truncating variant (Bakshi_2003). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002045343.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Oct 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889542.2
First in ClinVar: Mar 13, 2019 Last updated: Jan 03, 2022 |
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Pathogenic
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003928054.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
The NBN c.1142del (p.Pro381GlnfsTer23) change deletes one nucleotide and causes a frameshift and the creation of a premature stop codon. This change is predicted to … (more)
The NBN c.1142del (p.Pro381GlnfsTer23) change deletes one nucleotide 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 0.0053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported as compound heterozygous in an individuals affected with Nijmegen breakage syndrome (PMID: 9590180, 12621246). In addition, this variant has been identified in individuals with ovarian cancer (PMID: 22006311, 26315354, 29625052, 30322717). Two individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic. (less)
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000287446.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro381Glnfs*23) in the NBN gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Pro381Glnfs*23) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs587781969, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 9590180, 10799436, 12621246, 22006311, 24549055, 26315354). ClinVar contains an entry for this variant (Variation ID: 141731). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 15, 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
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Ambry Genetics
Accession: SCV000185206.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.1142delC pathogenic mutation, located in coding exon 10 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 1142, causing … (more)
The c.1142delC pathogenic mutation, located in coding exon 10 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 1142, causing a translational frameshift with a predicted alternate stop codon (p.P381Qfs*23). This alteration has been described in conjunction with a pathogenic founder mutation in at least one patient with Nijmegen breakage syndrome (Varon R et al. Cell. 1998 May;93:467-76). This alteration has also been reported in cohorts of patients with a personal and/or family history of breast and/or ovarian cancers (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 01, 1998)
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no assertion criteria provided
Method: literature only
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NIJMEGEN BREAKAGE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027557.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 01, 2016 |
Comment on evidence:
In a patient of Canadian origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a deletion of 1 nucleotide in exon 10 … (more)
In a patient of Canadian origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a deletion of 1 nucleotide in exon 10 of the NBS1 gene, resulting in a frameshift and a truncated protein. (less)
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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
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Natera, Inc.
Accession: SCV001460720.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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: SCV000494637.2
First in ClinVar: Jul 01, 2016 Last updated: Oct 01, 2022 |
Geographic origin: Canada
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Nijmegen Breakage Syndrome. | Adam MP | - | 2023 | PMID: 20301355 |
Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. | Desmond A | JAMA oncology | 2015 | PMID: 26270727 |
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. | Castéra L | European journal of human genetics : EJHG | 2014 | PMID: 24549055 |
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
Mutations in the Nijmegen breakage syndrome gene in medulloblastomas. | Huang J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18593981 |
Mild Nijmegen breakage syndrome phenotype due to alternative splicing. | Varon R | Human molecular genetics | 2006 | PMID: 16415040 |
Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome. | Bakhshi S | Journal of pediatric hematology/oncology | 2003 | PMID: 12621246 |
Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. | The I | Archives of disease in childhood | 2000 | PMID: 10799436 |
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 rs587781969 ...
HelpRecord last updated May 12, 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.