ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.9648+1G>A
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(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.9648+1G>A
Variation ID: 487418 Accession: VCV000487418.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32397045 (GRCh38) [ NCBI UCSC ] 13: 32971182 (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 Jan 7, 2018 Feb 28, 2024 Nov 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.9648+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001406719.1:c.9552+1G>A splice donor NM_001406720.1:c.9597+1G>A splice donor NM_001406721.1:c.4716+1G>A splice donor NM_001406722.1:c.3231+1G>A splice donor NC_000013.11:g.32397045G>A NC_000013.10:g.32971182G>A NG_012772.3:g.86566G>A LRG_293:g.86566G>A LRG_293t1:c.9648+1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000013.11:32397044:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on RNA splicing Variation Ontology [VariO:0362]
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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 |
18542 | 18699 |
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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Dec 12, 2022 | RCV000576826.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV003159971.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2023 | RCV003767249.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Pathogenic
(Dec 12, 2022)
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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: yes
Allele origin:
unknown
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Hereditary Cancer Unit, Hospital Universitario 12 de Octubre
Accession: SCV002760187.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
This variant is absent in the populations databases and has already been reported in scientific literature in a woman from a cohort of 7051 Japanese … (more)
This variant is absent in the populations databases and has already been reported in scientific literature in a woman from a cohort of 7051 Japanese breast cancer patients (Yukihide Momozawa, 2018). Additionally, functional studies performed in our laboratory conclude that c.9648+1G>A variant leads to the skipping of exon 26 of BRCA2 protein. A mouse embryonic stem cell (mESC)-based assay revealed that BRCA2 c.9648+1G>A causes exon 26 skipping (human BRCA2-containing BAC), and that in-frame exon 26 skipping does not complement removal of the conditional mBrca2 allele, supporting loss-of-function (Mesman RLS, 2020). This change is classified as pathogenic (Class 5) following the qualitative ACMG criteria since (i) it is absent in several population databases (PM2_Supporting) (ii) it is a GT-AG variant causing an in-frame alteration targeting a region critical to protein function (PVS1_O_Strong) and (iii) a well-stablished functional assay supports damage on gene product (PS3). Additionally, this change is classified as likely pathogenic (Class 4) following the quantitative ACMG point system in which PVS1_strong, PS3 and PM2_Supporting add up to 9 points (likely pathogenic: 6-9 point range). In summary, this variant meets our criteria to be classified as likely pathogenic. (less)
Age: 30-39 years
Sex: female
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Likely pathogenic
(Jan 16, 2017)
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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:
unknown
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Counsyl
Accession: SCV000677870.2
First in ClinVar: Jan 07, 2018 Last updated: Dec 24, 2022 |
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Uncertain significance
(Mar 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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Ambry Genetics
Accession: SCV003859073.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The c.9648+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 25 of the BRCA2 gene. Alterations that disrupt the … (more)
The c.9648+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 25 of the BRCA2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 49 amino acids (Gay-Bellile M et al. Clin Genet, 2020 Apr;97:668-669; Mesman RLS et al. Genet Med, 2020 Aug;22:1355-1365; Ambry internal data), however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). This variant has been detected in conjunction with a pathogenic finding in this same gene and confirmed in trans in two brothers with no reported features of Fanconi anemia (Gay-Bellile M et al. Clin Genet, 2020 Apr;97:668-669), suggesting that this allele may retain some normal BRCA2 activity. However, another study reported this alteration as non-functional, as it did not complement conditional loss of Brca2 activity in a cell viability assay performed in murine embryonic stem cells (mESCs) (Mesman RLS et al. Genet Med, 2020 Aug;22:1355-1365). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Nov 08, 2023)
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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: SCV004634283.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 26 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 26 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 31875949). ClinVar contains an entry for this variant (Variation ID: 487418). Studies have shown that disruption of this splice site alters BRCA2 gene expression (PMID: 32398771). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 26, but is expected to preserve the integrity of the reading-frame (PMID: 31875949, 32398771). 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. (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on RNA splicing
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Hereditary Cancer Unit, Hospital Universitario 12 de Octubre
Accession: SCV002760187.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Alternative mRNA splicing can attenuate the pathogenicity of presumed loss-of-function variants in BRCA2. | Mesman RLS | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | DOI: 10.1038/s41436-020-0814-5 |
Alternative mRNA splicing can attenuate the pathogenicity of presumed loss-of-function variants in BRCA2. | Mesman RLS | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32398771 |
Is BRCA2 involved in early onset colorectal cancer risk? | Gay-Bellile M | Clinical genetics | 2020 | PMID: 31875949 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | DOI: 10.1038/s41467-018-06581-8 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs730881573 ...
HelpRecord last updated Mar 30, 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.