ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8332-1G>T
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_000059.4(BRCA2):c.8332-1G>T
Variation ID: 185300 Accession: VCV000185300.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32370401 (GRCh38) [ NCBI UCSC ] 13: 32944538 (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 Mar 24, 2015 May 1, 2024 Aug 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8332-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001406719.1:c.8236-1G>T splice acceptor NM_001406720.1:c.8332-1G>T splice acceptor NM_001406721.1:c.3400-1G>T splice acceptor NM_001406722.1:c.1915-1G>T splice acceptor NC_000013.11:g.32370401G>T NC_000013.10:g.32944538G>T NG_012772.3:g.59922G>T LRG_293:g.59922G>T LRG_293t1:c.8332-1G>T - Protein change
- Other names
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- Canonical SPDI
- NC_000013.11:32370400:G: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.
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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 |
18951 | 19110 |
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
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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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV000164696.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 11, 2023 | RCV000258264.13 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 18, 2022 | RCV000586321.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2022 | RCV001311842.16 |
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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Likely pathogenic
(May 26, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695145.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The BRCA2 c.8332-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Variant summary: The BRCA2 c.8332-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a weakening of the canonical splice donor site while 3/5 splice prediction tools predict the variant to activate a cryptic splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant of interest has not been found in a large, broad control population, ExAC in 121260 control chromosomes. This variant was reported in one study in a BC patient with extensive BC history (Becker_Breast Cancer Res Treat_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 18, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001375007.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in deletion of 14 nucleotides of exon 19 and introduces a premature termination codon (PMID: 21735045). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 185300). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 22729890, 29446198, 30199306). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 18 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. (less)
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Pathogenic
(Mar 19, 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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Ambry Genetics
Accession: SCV000215364.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.8332-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 18 of the BRCA2 gene. This nucleotide … (more)
The c.8332-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 18 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was observed in an individuals with a personal and family history of early onset breast cancer (Becker AA et al. Breast Cancer Res. Treat., 2012 Aug;135:167-75; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor/acceptor site (c.8332-1G>A) has been shown to have a similar impact on splicing (Menéndez M et al. Breast Cancer Res Treat, 2012 Apr;132:979-92). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Aug 16, 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: SCV004362745.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to T nucleotide substitution at the -1 position of intron 18 of the BRCA2 gene. Splice site prediction tools predict … (more)
This variant causes a G to T nucleotide substitution at the -1 position of intron 18 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. A functional RNA study reported that a variant impacting the same splice site, c.8332-1G>C, causes a 14 nucleotide deletion in exon 19 and is expected to result in a frameshift and premature translation stop signal (PMID: 21735045). This variant has been reported in at least two individuals affected with breast cancer and an individual affected with pancreatic cancer (PMID: 22729890, 30199306, 33471991, 35171259). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jul 11, 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: SCV004833244.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.8332-1G>T variant in the BRCA2 gene is located at the canonical splice site of intron 18 and is predicted to inflict acceptor loss (SpliceAI … (more)
The c.8332-1G>T variant in the BRCA2 gene is located at the canonical splice site of intron 18 and is predicted to inflict acceptor loss (SpliceAI delta score: 0.99), resulting in alternative splicing and disrupted protein product. The variant has been reported in 3 unrelated individuals with breast/ pancreatic cancer (PMID: 29297111, 35171259, 22729890). Experimental analysis of cDNA showed that this variant abolishes the natural 3? splice site of exon 19 and leads to the activation of a cryptic splice site 14 bp downstream. The mutated transcript shows a 14-bp deletion at the beginning of exon 19. This change is predicted to generate a truncated protein (p.Ile2778Tyrfs*15) (PMID: 21735045). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar (ID: 185300). The variant is absent in the general population database (gnomAD). Therefore, the c.8332-1G>T variant of BRCA2 has been classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000327873.4
First in ClinVar: Nov 06, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Feb 01, 2022)
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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: SCV002073981.2
First in ClinVar: Feb 13, 2022 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, leading to the in-frame deletion of exon 19, which is located in the critical DSS1 … (more)
Canonical splice site variant expected to result in aberrant splicing, leading to the in-frame deletion of exon 19, which is located in the critical DSS1 contacting residue of the DNA binding domain (Yang 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 8560-1G>T; Observed in individuals with a personal or family history of breast cancer in published literature (Becker 2012, Abulkhair 2018); This variant is associated with the following publications: (PMID: 30199306, 22729890, 29446198) (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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Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China. | Yin L | JAMA network open | 2022 | PMID: 35171259 |
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 |
Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer. | Abulkhair O | Journal of global oncology | 2018 | PMID: 30199306 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
High prevalence of deleterious BRCA1 and BRCA2 germline mutations in arab breast and ovarian cancer patients. | Alhuqail AJ | Breast cancer research and treatment | 2018 | PMID: 29297111 |
A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity. | Becker AA | Breast cancer research and treatment | 2012 | PMID: 22729890 |
Assessing the RNA effect of 26 DNA variants in the BRCA1 and BRCA2 genes. | Menéndez M | Breast cancer research and treatment | 2012 | PMID: 21735045 |
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. | Hamann U | Journal of medical genetics | 2002 | PMID: 11897832 |
Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. | Gayther SA | Nature genetics | 1997 | PMID: 8988179 |
Text-mined citations for rs397507979 ...
HelpRecord last updated Oct 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.