ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.1146A>T (p.Lys382Asn)
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.1146A>T (p.Lys382Asn)
Variation ID: 96761 Accession: VCV000096761.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32332624 (GRCh38) [ NCBI UCSC ] 13: 32906761 (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 Sep 27, 2014 Apr 20, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.1146A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Lys382Asn missense NC_000013.11:g.32332624A>T NC_000013.10:g.32906761A>T NG_012772.3:g.22145A>T LRG_293:g.22145A>T LRG_293t1:c.1146A>T LRG_293p1:p.Lys382Asn - Protein change
- K382N
- Other names
- 1374A>T
- Canonical SPDI
- NC_000013.11:32332623:A:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18542 | 18699 |
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 (3) |
criteria provided, single submitter
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Oct 27, 2023 | RCV000082882.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 19, 2023 | RCV000130529.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 25, 2020 | RCV000486000.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV001036707.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 30, 2022 | RCV002498436.3 |
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
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 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Malignant tumor of prostate Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002794024.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 25, 2020)
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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: SCV000564762.5
First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as BRCA2 c.1374A>T; Observed in individuals with a personal or family history including breast cancer (Falchetti 2008); This variant is associated with the following publications: (PMID: 17661168, 23683081, 27150160) (less)
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Likely benign
(Mar 23, 2023)
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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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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003849871.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
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Uncertain significance
(Apr 19, 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: SCV000185398.8
First in ClinVar: Aug 06, 2014 Last updated: Jul 08, 2023 |
Comment:
The p.K382N variant (also known as c.1146A>T), located in coding exon 9 of the BRCA2 gene, results from an A to T substitution at nucleotide … (more)
The p.K382N variant (also known as c.1146A>T), located in coding exon 9 of the BRCA2 gene, results from an A to T substitution at nucleotide position 1146. The lysine at codon 382 is replaced by asparagine, an amino acid with similar properties. This alteration has been identified in multiple individuals undergoing genetic testing based on a personal and/or family history of HBOC-related cancers (Falchetti M et al. Breast Cancer Res. Treat. 2008;110(1):161-7; Gatti-Mays ME et al. Oncologist, 2020 12;25:1013-e1824; Bisgin A et al. Breast, 2022 Oct;65:15-22; Carvalho CM et al. Rev Bras Ginecol Obstet, 2023 Feb;45:74-81). Of note, this alteration is also known as 1374A>T and 1874A>T in published literature. This amino acid position is not well 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
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001200084.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 382 of the BRCA2 protein (p.Lys382Asn). … (more)
This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 382 of the BRCA2 protein (p.Lys382Asn). This variant is present in population databases (rs431825280, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 17661168). This variant is also known as c.1374A>T. ClinVar contains an entry for this variant (Variation ID: 96761). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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
(Oct 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846869.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces lysine with asparagine at codon 382 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces lysine with asparagine at codon 382 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast cancer, including 1 male individual (PMID: 17661168, 32510664) and in 4 suspected hereditary breast and ovarian cancer families (PMID: 31409081). This variant has been identified in 1/250216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 4
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Uncertain significance
(Feb 01, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000908932.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces lysine with asparagine at codon 382 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces lysine with asparagine at codon 382 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast cancer, including 1 male individual (PMID: 17661168, 32510664) and in 4 suspected hereditary breast and ovarian cancer families (PMID: 31409081). This variant has been identified in 1/250216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Sep 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228353.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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Uncertain significance
(May 01, 2012)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000114956.3
First in ClinVar: Feb 09, 2014 Last updated: Sep 27, 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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Germline Mutations Landscape in a Cohort of the State of Minas Gerais, Brazil, in Patients Who Underwent Genetic Counseling for Gynecological and Breast Cancer. | Carvalho CM | Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia | 2023 | PMID: 36977404 |
Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey. | Bisgin A | Breast (Edinburgh, Scotland) | 2022 | PMID: 35753294 |
A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer. | Gatti-Mays ME | The oncologist | 2020 | PMID: 32510664 |
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
Twenty Years of BRCA1 and BRCA2 Molecular Analysis at MMCI - Current Developments for the Classification of Variants. | Machackova E | Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti | 2019 | PMID: 31409081 |
BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. | Falchetti M | Breast cancer research and treatment | 2008 | PMID: 17661168 |
Text-mined citations for rs431825280 ...
HelpRecord last updated Apr 20, 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.