ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.1903A>T (p.Lys635Ter)
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.1903A>T (p.Lys635Ter)
Variation ID: 142559 Accession: VCV000142559.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 89947835 (GRCh38) [ NCBI UCSC ] 8: 90960063 (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 1, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002485.5:c.1903A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Lys635Ter nonsense NM_001024688.3:c.1657A>T NP_001019859.1:p.Lys553Ter nonsense NC_000008.11:g.89947835T>A NC_000008.10:g.90960063T>A NG_008860.1:g.41837A>T LRG_158:g.41837A>T LRG_158t1:c.1903A>T LRG_158p1:p.Lys635Ter - Protein change
- K635*, K553*
- Other names
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- Canonical SPDI
- NC_000008.11:89947834:T:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00005
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 | ||
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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
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. |
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NBN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3381 | 3553 | |
LOC126860438 | - | - | - | GRCh38 | - | 145 |
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. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV000131755.13 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV000219708.10 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2024 | RCV000227700.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763606.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2023 | RCV003467185.1 |
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
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. |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Aplastic anemia Acute lymphoid leukemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894452.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 14, 2019)
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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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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448749.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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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: SCV002045315.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Oct 23, 2019)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002067395.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the NBN gene demonstrated a sequence change, c.1903A>T, which results in the creation of a premature stop codon at amino acid … (more)
DNA sequence analysis of the NBN gene demonstrated a sequence change, c.1903A>T, which results in the creation of a premature stop codon at amino acid position 635, p.Lys635*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NBN protein with potentially abnormal function. This pathogenic sequence change has been previously described in two patients with breast and pancreatic cancer (PMIDs: 28727877, 29506128). (less)
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Likely pathogenic
(Apr 25, 2016)
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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: SCV000486262.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Feb 21, 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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GeneDx
Accession: SCV000279419.14
First in ClinVar: May 29, 2016 Last updated: Mar 11, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense 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: 24763289, 29506128, 28727877, 30716324, 31589614, 31980526, 30322717, 31341520, 29922827) (less)
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Pathogenic
(Oct 14, 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: SCV004199531.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 12, 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: SCV000287457.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys635*) 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.Lys635*) 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 (rs587782545, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with breast cancer, pancreatic cancer, and/or ovarian cancer (PMID: 28727877, 29506128, 30322717). ClinVar contains an entry for this variant (Variation ID: 142559). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 06, 2022)
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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: SCV000186798.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.K635* pathogenic mutation (also known as c.1903A>T), located in coding exon 12 of the NBN gene, results from an A to T substitution at … (more)
The p.K635* pathogenic mutation (also known as c.1903A>T), located in coding exon 12 of the NBN gene, results from an A to T substitution at nucleotide position 1903. This changes the amino acid from a lysine to a stop codon within coding exon 12. This alteration was reported in a cohort of 1007 Ashkenazi Jewish women with breast cancer who underwent multi-gene panel testing in one woman with breast cancer diagnosed at age 42 (Walsh T et al. JAMA Oncol. 2017 Dec;3:1647-1653). This alteration was also reported in 1/615 individuals with pancreatic cancer who underwent multi-gene panel testing (Lowery MA et al J. Natl. Cancer Inst. 2018 Oct;110:1067-1074). In addition to the information 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
(Aug 20, 2020)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537637.3
First in ClinVar: Sep 24, 2016 Last updated: Jun 19, 2021 |
Comment:
This variant changes 1 nucleotide in exon 12 of the NBN gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 12 of the NBN gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individuals affected with breast or pancreatic cancer (PMID: 28727877, 29506128). This variant has been identified in 9/233100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of NBN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Jan 24, 2023)
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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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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV004014980.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
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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: SCV001456588.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. | Lowery MA | Journal of the National Cancer Institute | 2018 | PMID: 29506128 |
Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women. | Walsh T | JAMA oncology | 2017 | PMID: 28727877 |
Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. | LaDuca H | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24763289 |
Mild Nijmegen breakage syndrome phenotype due to alternative splicing. | Varon R | Human molecular genetics | 2006 | PMID: 16415040 |
Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. | Varon R | Cell | 1998 | PMID: 9590180 |
Text-mined citations for rs587782545 ...
HelpRecord last updated May 01, 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.