ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.67+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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.67+1G>A
Variation ID: 52160 Accession: VCV000052160.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32316528 (GRCh38) [ NCBI UCSC ] 13: 32890665 (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 Apr 1, 2014 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.67+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001406719.1:c.67+1G>A splice donor NM_001406720.1:c.67+1G>A splice donor NM_001406721.1:c.67+1G>A splice donor NM_001406722.1:c.-303+861G>A intron variant NC_000013.11:g.32316528G>A NC_000013.10:g.32890665G>A NG_012772.3:g.6049G>A NG_017006.2:g.3836C>T LRG_293:g.6049G>A LRG_293t1:c.67+1G>A U43746.1:n.295+1G>A - Protein change
- Other names
- IVS2+1G>A
- Canonical SPDI
- NC_000013.11:32316527:G:A
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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 |
18955 | 19114 |
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 (3) |
criteria provided, single submitter
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Oct 2, 2015 | RCV000077381.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000218090.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2023 | RCV000496390.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2023 | RCV000510076.13 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV003332101.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV003162384.10 |
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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Pathogenic
(Apr 06, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511908.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: BRCA2 c.67+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered … (more)
Variant summary: BRCA2 c.67+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon skipping (example, Bonatti_2006). The variant was absent in 250582 control chromosomes. c.67+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 31, 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: SCV004220516.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. It is reported to cause the skipping of exon 2 during … (more)
This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. It is reported to cause the skipping of exon 2 during splicing, resulting in a truncated protein product (PMID: 17011978 (2006)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 35220195 (2022), 32658311 (2021), 32599251 (2020), 32438681 (2020), 32058061 (2020), 32846166 (2020), 28888541 (2017), 21063910 (2011), and 12938098 (2003)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 19, 2015)
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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: SCV000279587.9
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
This variant is denoted BRCA2 c.67+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the BRCA2 … (more)
This variant is denoted BRCA2 c.67+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the BRCA2 gene. This variant destroys a canonical splice donor site and causes exon 2 skipping, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonatti 2006). This variant, also defined as BRCA2 295+1G>A using alternate nomenclature, has been reported in individuals with a personal and family history of early-onset breast and/or ovarian cancer and has been described as a founder pathogenic variant in the Sephardic Jewish population (Bonatti 2006, Sagi 2011, Balabanski 2014). We consider this variant to be pathogenic. (less)
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Pathogenic
(Dec 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004210424.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591718.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 2 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 2 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 17011978, 21063910, 32058061, 32846166). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 52160). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 17011978, 22505045). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 15, 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: SCV000608123.6
First in ClinVar: Oct 23, 2017 Last updated: May 01, 2024 |
Comment:
The c.67+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the BRCA2 gene. This mutation has … (more)
The c.67+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the BRCA2 gene. This mutation has previously been reported in three families of Sephardic origin affected with breast and/or ovarian cancer (Sagi M et al. Fam. Cancer. 2011 Mar;10(1):59-63). Functional analysis of this alteration using an RNA based assay showed skipping of coding exon 1 and truncation of the BRCA2 protein (Ambry internal data; Bonatti F et al. Cancer Genet. Cytogenet. 2006 Oct;170(2):93-101). Further, an alteration at the same location (c.67+1G>T) has been reported in a German family affected with breast and/or ovarian cancer (Meyer P et al. Hum. Mutat. 2003 Sep;22(3):259). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 classified as a disease-causing mutation. (less)
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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: SCV000327501.4
First in ClinVar: Sep 27, 2014 Last updated: Dec 11, 2022 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003914731.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Clinical Features:
Breast carcinoma (present)
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Pathogenic
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090005.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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Pathogenic
(Jun 21, 1999)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146093.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Pathogenic
(Nov 25, 2008)
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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: SCV000109178.2
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587532.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Malignant tumor of urinary bladder
Affected status: yes
Allele origin:
somatic
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Laboratory of Urology, Hospital Clinic de Barcelona
Accession: SCV004040594.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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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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Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey. | Bora E | Cancer genetics | 2022 | PMID: 35220195 |
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
Next generation sequencing analysis of BRCA1 and BRCA2 identifies novel variations in breast cancer. | Yildiz Tacar S | Life sciences | 2020 | PMID: 32846166 |
Characterization and in silico analyses of the BRCA1/2 variants identified in individuals with personal and/or family history of BRCA-related cancers. | Pirim D | International journal of biological macromolecules | 2020 | PMID: 32599251 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
BRCA and PALB2 mutations in a cohort of male breast cancer with one bilateral case. | Vietri MT | European journal of medical genetics | 2020 | PMID: 32058061 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. | Lilyquist J | Gynecologic oncology | 2017 | PMID: 28888541 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
Two BRCA1/2 founder mutations in Jews of Sephardic origin. | Sagi M | Familial cancer | 2011 | PMID: 21063910 |
RNA-based analysis of BRCA1 and BRCA2 gene alterations. | Bonatti F | Cancer genetics and cytogenetics | 2006 | PMID: 17011978 |
Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany. | Meyer P | Human mutation | 2003 | PMID: 12938098 |
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Text-mined citations for rs81002796 ...
HelpRecord last updated Oct 13, 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.