ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.2215C>G (p.Leu739Val)
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.2215C>G (p.Leu739Val)
Variation ID: 182730 Accession: VCV000182730.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 89937045 (GRCh38) [ NCBI UCSC ] 8: 90949273 (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 Feb 19, 2018 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002485.5:c.2215C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Leu739Val missense NM_001024688.3:c.1969C>G NP_001019859.1:p.Leu657Val missense NC_000008.11:g.89937045G>C NC_000008.10:g.90949273G>C NG_008860.1:g.52627C>G LRG_158:g.52627C>G LRG_158t1:c.2215C>G LRG_158p1:p.Leu739Val - Protein change
- L739V, L657V
- Other names
- p.L739V:CTT>GTT
- Canonical SPDI
- NC_000008.11:89937044:G:C
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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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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
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. |
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NBN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3381 | 3553 |
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 24, 2023 | RCV000160797.15 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000168129.20 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2023 | RCV000590749.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 29, 2021 | RCV000764782.4 |
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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Uncertain significance
(Nov 29, 2021)
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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: SCV000895926.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Uncertain significance
(Feb 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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Ambry Genetics
Accession: SCV000215461.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.L739V variant (also known as c.2215C>G), located in coding exon 15 of the NBN gene, results from a C to G substitution at nucleotide … (more)
The p.L739V variant (also known as c.2215C>G), located in coding exon 15 of the NBN gene, results from a C to G substitution at nucleotide position 2215. The leucine at codon 739 is replaced by valine, an amino acid with highly similar properties. This variant was detected in 1/160 children with newly diagnosed cancer. This patient was diagnosed with pilocytic astrocytoma (Wagener R et al. Eur J Hum Genet, 2021 Aug;29:1301-1311). This variant was also reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Apr 10, 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: SCV000211462.17
First in ClinVar: Feb 24, 2015 Last updated: Apr 15, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a pediatric astrocytoma patient (Wagener et al., 2021); This variant … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a pediatric astrocytoma patient (Wagener et al., 2021); This variant is associated with the following publications: (PMID: 24894818, 33840814) (less)
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Uncertain significance
(Jul 18, 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: SCV004031232.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
The NBN c.2215C>G (p.Leu739Val) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The NBN c.2215C>G (p.Leu739Val) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in a large case-control study of breast cancer in 3 of 60,466 cases and 2 of 53,461 controls (PMID: 33471991). This variant has been reported in two siblings who developed pilocytic astrocytoma and Hodgkin lymphoma at ten years and eighteen years of age, respectively. Four individuals with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Nijmegan breakage syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Jan 18, 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: SCV000218788.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 739 of the NBN protein (p.Leu739Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 739 of the NBN protein (p.Leu739Val). This variant is present in population databases (rs370058152, gnomAD 0.006%). This missense change has been observed in individual(s) with Hodgkin's lymphoma (PMID: 33840814). ClinVar contains an entry for this variant (Variation ID: 182730). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Feb 01, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697964.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.2215C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 2/4 in-silico tools predict this variant to … (more)
Variant summary: The c.2215C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 3/115508 control chromosomes at a frequency of 0.000026, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0025). In addition, multiple clinical laboratories classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. (less)
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Uncertain significance
(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: SCV002046027.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Uncertain significance
(Jun 25, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002536646.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NBN c.2215C>G (p.L739V) variant has been reported in 3/60466 breast cancer cases and 2/53461 healthy controls by a large case-control study (PMID: 33471991). The … (more)
The NBN c.2215C>G (p.L739V) variant has been reported in 3/60466 breast cancer cases and 2/53461 healthy controls by a large case-control study (PMID: 33471991). The variant was also reported in two siblings who developed pilocytic astrocytoma and a Hodgkin lymphoma, respectively (PMID: 33840814). It was observed in 7/113132 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 182730). In silico tools suggest the impact of the variant on protein function is inconclusive though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jul 02, 2018)
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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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Mendelics
Accession: SCV000838295.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010438.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Feb 21, 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: SCV002078498.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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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 |
Text-mined citations for rs370058152 ...
HelpRecord last updated May 08, 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.