ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.1591A>G (p.Ile531Val)
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.
Uncertain significance(4); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002485.5(NBN):c.1591A>G (p.Ile531Val)
Variation ID: 142242 Accession: VCV000142242.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 89953498 (GRCh38) [ NCBI UCSC ] 8: 90965726 (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 Dec 26, 2017 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002485.5:c.1591A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Ile531Val missense NM_001024688.3:c.1345A>G NP_001019859.1:p.Ile449Val missense NC_000008.11:g.89953498T>C NC_000008.10:g.90965726T>C NG_008860.1:g.36174A>G LRG_158:g.36174A>G LRG_158t1:c.1591A>G LRG_158p1:p.Ile531Val - Protein change
- I531V, I449V
- Other names
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- Canonical SPDI
- NC_000008.11:89953497:T: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00001
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
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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Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000131247.10 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2023 | RCV000542468.14 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001357760.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 15, 2021 | RCV001778752.3 |
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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Uncertain significance
(Oct 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002014925.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: NBN c.1591A>G (p.Ile531Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: NBN c.1591A>G (p.Ile531Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1591A>G has been reported in the literature as a VUS in settings of multigene cancer panel testing in one out of 36 individuals personal and/or family history of cancer (Cabanillas_2017) and in a woman with breast cancer (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4, likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (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: SCV002045907.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Uncertain significance
(Jun 02, 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:
unknown
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Mendelics
Accession: SCV001137661.2
First in ClinVar: Jan 09, 2020 Last updated: Jun 03, 2023 |
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Uncertain significance
(Nov 05, 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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Invitae
Accession: SCV000634238.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 531 of the NBN protein (p.Ile531Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 531 of the NBN protein (p.Ile531Val). This variant is present in population databases (rs587782330, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 142242). 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 tolerated. 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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Likely benign
(Feb 01, 2024)
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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: SCV000186206.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(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: SCV001456596.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(-)
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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: SCV001553324.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The NBN p.Ile531Val variant was identified in 1 of 72 proband chromosomes (frequency: 0.01) from individuals or families with a personal and/or family history of … (more)
The NBN p.Ile531Val variant was identified in 1 of 72 proband chromosomes (frequency: 0.01) from individuals or families with a personal and/or family history of cancer (Cabanillas 2017). The variant was also identified in dbSNP (ID: rs587782330) “With Uncertain significance allele”, ClinVar (classified uncertain significance by Ambry Genetics, Invitae and Color Genomics Inc.), and Clinvitae (2x), and was not identified in Cosmic, LOVD 3.0, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 6 of 245818 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5474 chromosomes (freq: 0.0002), Latino in 1 of 33568 chromosomes (freq: 0.00003), European Non-Finnish in 2 of 111370 chromosomes (freq: 0.00002), and South Asian in 2 of 30766 chromosomes (freq: 0.00007); it not observed in the African, Ashkenazi Jewish, East Asian and European Finnish populations. The p.Ile531 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Val impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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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 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
A novel molecular diagnostics platform for somatic and germline precision oncology. | Cabanillas R | Molecular genetics & genomic medicine | 2017 | PMID: 28717660 |
Text-mined citations for rs587782330 ...
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.