ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.1262T>C (p.Leu421Ser)
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(7); Benign(2); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002485.5(NBN):c.1262T>C (p.Leu421Ser)
Variation ID: 127009 Accession: VCV000127009.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 89955418 (GRCh38) [ NCBI UCSC ] 8: 90967646 (GRCh37) [ NCBI UCSC ] 8: 91036822 (NCBI36) [ 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 Apr 24, 2014 May 1, 2024 Jan 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002485.5:c.1262T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Leu421Ser missense NM_001024688.2:c.1016T>C NM_001024688.3:c.1016T>C NP_001019859.1:p.Leu339Ser missense NC_000008.11:g.89955418A>G NC_000008.10:g.90967646A>G NC_000008.9:g.91036822A>G NG_008860.1:g.34254T>C LRG_158:g.34254T>C LRG_158t1:c.1262T>C LRG_158p1:p.Leu421Ser - Protein change
- L421S, L339S
- Other names
- p.L421S:TTG>TCG
- Canonical SPDI
- NC_000008.11:89955417:A: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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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00026
The Genome Aggregation Database (gnomAD) 0.00027
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
Exome Aggregation Consortium (ExAC) 0.00037
The Genome Aggregation Database (gnomAD), exomes 0.00037
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
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. |
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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
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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Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Jan 12, 2023 | RCV000114875.19 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 10, 2023 | RCV000115780.18 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV000123203.31 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2021 | RCV000212745.9 | |
Likely benign (1) |
criteria provided, single submitter
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May 29, 2018 | RCV000757930.5 | |
Likely benign (1) |
no assertion criteria provided
|
- | RCV001358304.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2017 | RCV000515275.4 |
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
(May 03, 2018)
|
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: SCV000799755.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Likely benign
(Jun 28, 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: SCV000697942.2
First in ClinVar: Apr 24, 2014 Last updated: Jul 10, 2021 |
Comment:
Variant summary: NBN c.1262T>C (p.Leu421Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: NBN c.1262T>C (p.Leu421Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 260122 control chromosomes in the gnomAD database, including 1 homozygote. The variant was also reported in 7 European American women older than age 70 years who have never had cancer. This data provide supporting evidence for a benign role. c.1262T>C has been reported in the literature in individuals affected with CVID, OvC, HBOC, Lynch syndrome and PDAC (e.g. Offer_2010, Ramus_2015, Tung_2015, Yurgelun_2015, 2017, Chaffee_2018, Dorling_2021) but it was also reported in multiple controls (Offer_2010, Ramus_2015, Dorling_2021). Additionally, evidence of non co-segregation with disease was provided through the study of a large family affected with different types of cancer including breast cancer (Tsai_2019), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and eight ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(May 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149689.12
First in ClinVar: May 17, 2014 Last updated: Dec 06, 2016 |
Comment:
This variant is associated with the following publications: (PMID: 25980754, 26315354, 23555315, 20805886, 28135145, 28873162, 28726808, 30374176, 31278556)
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Benign
(Feb 13, 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: SCV002536582.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Mar 21, 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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Ambry Genetics
Accession: SCV000183761.8
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
(May 23, 2017)
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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: SCV000611485.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Uncertain significance
(Sep 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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GeneID Lab - Advanced Molecular Diagnostics
Accession: SCV000680451.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Number of individuals with the variant: 1
Age: 40-49 years
Sex: female
Ethnicity/Population group: Ashkenazi Jewish
Geographic origin: United States
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Uncertain significance
(Sep 08, 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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PreventionGenetics, part of Exact Sciences
Accession: SCV000806410.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 |
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Likely benign
(May 29, 2018)
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criteria provided, single submitter
Method: research
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Hereditary Breast Carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000886451.1
First in ClinVar: Feb 23, 2019 Last updated: Feb 23, 2019 |
Comment:
The NBN variant designated as NM_002485.4: c.1262T>C (p.Leu421Ser) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et … (more)
The NBN variant designated as NM_002485.4: c.1262T>C (p.Leu421Ser) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and yields a likelihood ratio of 1.88 to 1 that the allele is causing cancer in the family (Thompson et al, 2003, PMID:2900794, Damiola et al, 2014, PMID:24894818). However, this variant is found in approximately 1 out of 120 individuals of Ashkenazi Jewish ancestry (exac.broadinstitute.org), which is a higher frequency than expected of a pathogenic NBN variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 127009) and has been classified as benign by another clinical laboratory. Computer software programs also predict that this variant is likely to be tolerated. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter NBN function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. (less)
Family history: yes
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Uncertain significance
(May 28, 2019)
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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: SCV001137663.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Uncertain significance
(Jan 13, 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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000475294.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely benign
(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
|
Genome-Nilou Lab
Accession: SCV002045927.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Likely benign
(Dec 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002071521.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Jan 10, 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: SCV002819156.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
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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: SCV002011228.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
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Likely benign
(Jan 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046113.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
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Benign
(Jan 31, 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: SCV000166508.13
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024 |
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Uncertain significance
(Sep 28, 2018)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000886692.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797367.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
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Likely benign
(-)
|
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: SCV001554001.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The NBN p.Leu421Ser variant was identified in 5 of 11992 proband chromosomes (frequency: 0.0004) from individuals or families with antibody deficiency syndromes IgAD or CVID, … (more)
The NBN p.Leu421Ser variant was identified in 5 of 11992 proband chromosomes (frequency: 0.0004) from individuals or families with antibody deficiency syndromes IgAD or CVID, ovarian cancer or Lynch syndrome and was present in 3 of 8746 control chromosomes (frequency: 0.0005) from healthy individuals (Offer 2010, Ramus 2015, Yurgelun 2015, Yurgelun 2017). The variant was also found in Genome-Wide testing of putative functional exonic variants with relative risk 1.224 and P=0.87 (Haiman 2013). The variant was identified in dbSNP (ID: rs104895032) as "With other allele", and in ClinVar (classified as benign by Invitae; as uncertain significance by eight submitters). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 105 of 277090 chromosomes (1 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24016 chromosomes (freq: 0.0003), Other in 3 of 6458 chromosomes (freq: 0.0005), Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 44 of 126620 chromosomes (freq: 0.0004), Ashkenazi Jewish in 43 of 10152 chromosomes (freq: 0.004), Finnish in 8 of 25790 chromosomes (freq: 0.0003), while the variant was not observed in the East Asian, and South Asian populations. The p.Leu421 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966880.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978103.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Benign
(Nov 11, 2019)
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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: SCV002078588.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
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not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Harris Lab, University of Minnesota
Accession: SCV000148770.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 |
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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 |
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. | Tavtigian SV | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29300386 |
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. | Chaffee KG | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28726808 |
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 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
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 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. | Offer SM | PloS one | 2010 | PMID: 20805886 |
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Text-mined citations for rs104895032 ...
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.