ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7618-1G>A
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.7618-1G>A
Variation ID: 38110 Accession: VCV000038110.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32357741 (GRCh38) [ NCBI UCSC ] 13: 32931878 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 17, 2024 Aug 10, 2015 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.7618-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001406719.1:c.7522-1G>A splice acceptor NM_001406720.1:c.7618-1G>A splice acceptor NM_001406721.1:c.2686-1G>A splice acceptor NM_001406722.1:c.1201-1G>A splice acceptor NC_000013.11:g.32357741G>A NC_000013.10:g.32931878G>A NG_012772.3:g.47262G>A LRG_293:g.47262G>A LRG_293t1:c.7618-1G>A - Protein change
- Other names
- IVS15-1G>A
- Canonical SPDI
- NC_000013.11:32357740:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
---|---|---|---|---|---|---|
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. |
|||
BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18951 | 19110 |
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. |
---|---|---|---|---|
Pathogenic (5) |
reviewed by expert panel
|
Aug 10, 2015 | RCV000031692.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 24, 2022 | RCV000045265.26 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 22, 2023 | RCV000131688.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000195358.22 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 10, 2024 | RCV000474278.10 | |
Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2019 | RCV001171446.11 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Aug 10, 2015)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial 2
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000244474.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 (less)
|
|
Pathogenic
(Jun 10, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695083.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The BRCA2 c.7618-1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools predicting a significant impact on splicing, … (more)
Variant summary: The BRCA2 c.7618-1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools predicting a significant impact on splicing, which is functionally supported. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. (less)
|
|
Pathogenic
(Sep 23, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002531875.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.7618-1G>A variant has been reported in heterozygous state in at least two individuals with breast cancers (PMID: 21394826, 26681312). This variant has also … (more)
The BRCA2 c.7618-1G>A variant has been reported in heterozygous state in at least two individuals with breast cancers (PMID: 21394826, 26681312). This variant has also been reported in an individual with peritoneal cancer (PMID: 22006311). This variant affects a nucleotide within a consensus splice site of an intron and is predicted to cause abnormal gene splicing. Experimental studies have shown that this variant results in aberrant splicing by RNA and minigene assays (PMID: 21394826, 29881398). Loss of function variants in BRCA2 are known to be pathogenic (PMID: 29446198). It is also known as c.7846-1G>A and IVS15-1G>A in the literature. This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 38110). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(May 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210435.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: causes aberrant … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: causes aberrant splicing resulting in multiple transcripts, including partial deletion of exon 16 and exon 17, predicted to result in a null allele (Whiley 2011, Fraile-Bethencourt 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Murphy 2002, Walsh 2011, Tung 2016); Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7846-1G>A; This variant is associated with the following publications: (PMID: 12097290, 20104584, 30832263, 21990134, 21394826, 22006311, 17924331, 25085752, 26976419, 26681312, 29881398, 24240112, 23725378, 29446198, 28492532, 31843900, 31447099, 32398771, 30787465) (less)
|
|
Pathogenic
(Mar 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000540996.2
First in ClinVar: Apr 17, 2017 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Apr 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002504862.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
|
|
Pathogenic
(Sep 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600761.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, this variant has been reported in individuals … (more)
This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21394826 (2011), 22006311 (2011), 29881398 (2018)) and peritoneal cancer (PMID: 22006311 (2011)). Functional studies of this variant show abnormal splicing that results in a disrupted protein product (PMIDs: 21394826 (2011) and 29881398 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683894.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame … (more)
This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame splicing in the RNA from carriers of this variant, resulting in premature truncation (PMID: 21394826, 22006311, 31843900). This variant has been detected in at least 4 individuals affected with breast, pancreatic and peritoneal cancer (PMID: 12097290, 22006311, 26681312, 35451682) and has been identified in 11 families among the CIMBA participants (PMID: 29446198). 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 Pathogenic. (less)
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000073278.14
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 15 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 15 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 and peritoneal carcinoma (PMID: 21394826, 22006311, 26681312). This variant is also known as c.7846-1G>A and IVS15-1G>A. ClinVar contains an entry for this variant (Variation ID: 38110). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21394826, 21990134). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21394826, 22006311; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jun 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677711.2
First in ClinVar: Sep 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Aug 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023596.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000327695.4
First in ClinVar: Sep 29, 2015 Last updated: Dec 11, 2022 |
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004814338.1
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)
|
Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame … (more)
This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame splicing in the RNA from carriers of this variant, resulting in premature truncation (PMID: 21394826, 22006311, 31843900). This variant has been detected in at least 4 individuals affected with breast, pancreatic and peritoneal cancer (PMID: 12097290, 22006311, 26681312, 35451682) and has been identified in 11 families among the CIMBA participants (PMID: 29446198). 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 Pathogenic. (less)
Number of individuals with the variant: 2
|
|
Pathogenic
(Apr 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186724.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.7618-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 15 in the BRCA2 gene. This alteration has … (more)
The c.7618-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 15 in the BRCA2 gene. This alteration has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7). RNA and minigene assays have shown that this alteration results in a majority of transcript lacking 45bp from coding exon 14 (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Fraile-Bethencourt et al. Front Genet 2018 May;9:188). Of note, this alteration is also designated as IVS15-1G>A in published literature. 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)
|
|
Pathogenic
(Dec 09, 2010)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000054299.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
|
|
Pathogenic
(Sep 01, 2019)
|
no assertion criteria provided
Method: research
|
Hereditary breast and ovarian cancer syndrome
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV001251357.1
First in ClinVar: Jun 08, 2020 Last updated: Jun 08, 2020
Comment:
Transcript analysis by cBROCA
|
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective. | Molina-Zayas M | Molecular genetics and genomics : MGG | 2022 | PMID: 35451682 |
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 |
Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
Identification of Eight Spliceogenic Variants in BRCA2 Exon 16 by Minigene Assays. | Fraile-Bethencourt E | Frontiers in genetics | 2018 | PMID: 29881398 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. | Pennington KP | Clinical cancer research : an official journal of the American Association for Cancer Research | 2014 | PMID: 24240112 |
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary. | Whiley PJ | Human mutation | 2011 | PMID: 21394826 |
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. | Murphy KM | Cancer research | 2002 | PMID: 12097290 |
http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.7618-1G%3EA | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs397507389 ...
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.