ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8754G>A (p.Glu2918=)
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.8754G>A (p.Glu2918=)
Variation ID: 52671 Accession: VCV000052671.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32376791 (GRCh38) [ NCBI UCSC ] 13: 32950928 (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 May 1, 2024 Jul 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8754G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu2918= synonymous NC_000013.11:g.32376791G>A NC_000013.10:g.32950928G>A NG_012772.3:g.66312G>A LRG_293:g.66312G>A LRG_293t1:c.8754G>A LRG_293p1:p.Glu2918= U43746.1:n.8982G>A - Protein change
- Other names
- E2918E
- 8982G>A
- Canonical SPDI
- NC_000013.11:32376790: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.
The Genome Aggregation Database (gnomAD), exomes 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 |
18723 | 18881 |
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 | RCV000077451.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2021 | RCV000131042.14 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2022 | RCV000523204.12 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2023 | RCV000496546.15 |
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
(Jul 13, 2017)
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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: SCV000619052.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
This variant is denoted BRCA2 c.8754G>A at the DNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 2918, … (more)
This variant is denoted BRCA2 c.8754G>A at the DNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 2918, it has been demonstrated to cause abnormal splicing. Located at thelast nucleotide of exon 21, it disrupts a natural splice donor site and was found to cause abnormal splicing wheninterrogated via minigene assay (Acedo 2014). This variant, also reported as BRCA2 8982G>A using alternatenomenclature, has been published in at least one individual reported to have Hereditary Breast and Ovarian Cancersyndrome (Finkelman 2012). In addition, nearby variants found to cause the same impact on splicing have beenreported in association with Hereditary Breast and Ovarian Cancer (Brandão 2011). BRCA2 c.8754G>A was notobserved in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek2016). The nucleotide which is altered, a guanine (G) at base 8754, is conserved across species. Based on currentlyavailable information, we consider BRCA2 c.8754G>A to be likely pathogenic (less)
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Likely pathogenic
(Dec 15, 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: SCV002819555.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: BRCA2 c.8754G>A (p.Glu2918Glu) alters the conserved last nucleotide of exon 21 and therefore could affect mRNA splicing, leading to a significantly altered protein … (more)
Variant summary: BRCA2 c.8754G>A (p.Glu2918Glu) alters the conserved last nucleotide of exon 21 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to a shift in the reading frame (Acedo_2015). The variant allele was found at a frequency of 4e-06 in 250952 control chromosomes. c.8754G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Sambiasi_2014 Kaur_2018, Rebbeck_2018, Finkelman_2012). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jul 07, 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: SCV001576245.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs80359803, gnomAD 0.003%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data … (more)
This variant is present in population databases (rs80359803, gnomAD 0.003%). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25382762). ClinVar contains an entry for this variant (Variation ID: 52671). This variant is also known as E2918E. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22430266, 24145998, 29700634, 31454914). This sequence change affects codon 2918 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. (less)
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Likely Pathogenic
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848891.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Glu2918Glu variant in BRCA2 has been reported in at least 13 individuals with BRCA2-associated cancers, including at least 1 male with breast cancer, and … (more)
The p.Glu2918Glu variant in BRCA2 has been reported in at least 13 individuals with BRCA2-associated cancers, including at least 1 male with breast cancer, and segregated with disease in 2 affected relatives from 1 family (Kaur 2018 PMID: 29700634, Millan Catalan 2019 PMID: 31454914, Bapat 2021 medRxiv 2021.07.01.21258680; doi: https://doi.org/10.1101/2021.07.01.21258680). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 52671) and was absent from large population studies. Although it is a synonymous (silent) variant, it is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, which is corroborated by an in vitro minigene assay that indicates that this synonymous change disrupts normal splicing and results in an aberrant transcript that is subjected to nonsense-mediated decay (Acedo 2015 PMID: 25382762). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting. (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: SCV000327958.4
First in ClinVar: Sep 27, 2014 Last updated: Dec 11, 2022 |
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Likely pathogenic
(Oct 27, 2022)
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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: SCV001133947.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. The frequency of this variant in the general population, 0.000004 (1/250952 … (more)
This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. The frequency of this variant in the general population, 0.000004 (1/250952 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 29700634 (2018), 31454914 (2019)). It was also identified in individuals at-risk for breast/ovarian cancer (PMID: 22430266 (2012), 29446198 (2018)). Additionally, the authors of an in vitro minigene study observed that the variant abrogated the splice site completely and inserted noncoding sequence from the intron, including a premature stop codon, into the mRNA (PMID: 25382762 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 24, 2021)
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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: SCV000185972.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.8754G>A pathogenic variant (also known as p.E2918E), located in coding exon 20 of the BRCA2 gene, results from a G to A substitution at … (more)
The c.8754G>A pathogenic variant (also known as p.E2918E), located in coding exon 20 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8754. This nucleotide substitution does not change the glutamic acid at codon 2918. However, this change occurs in the last base pair of coding exon 20, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in numerous breast cancer cohorts (Finkelman BS et al. J. Clin. Oncol., 2012 Apr;30:1321-8; Kaur RP et al. Med. Oncol., 2018 Apr;35:81; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Multiple different RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Acedo A et al. Hum. Mutat., 2015 Feb;36:210-21). In addition, many other non-canonical splice alterations have been identified at this donor site and are also known to lead to a complete aberrant splice defect (Colombo M et al. PLoS One, 2013 Feb;8:e57173; Brandão RD et al. Breast Cancer Res Treat, 2011 Oct;129:971-82; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Bonatti F et al. Cancer Genet Cytogenet, 2006 Oct;170:93-101; Houdayer C et al. Hum Mutat, 2012 Aug;33:1228-38; Acedo A et al. Hum Mutat, 2015 Feb;36:210-21; Hendriks G et al. Hum Mutat, 2014 Nov;35:1382-91). 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 and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 10, 2000)
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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: SCV000147451.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean
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Pathogenic
(Apr 15, 2010)
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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: SCV000109249.3
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: SCV000587968.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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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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A Multi-Center Study of BRCA1 and BRCA2 Germline Mutations in Mexican-Mestizo Breast Cancer Families Reveals Mutations Unreported in Latin American Population. | Millan Catalan O | Cancers | 2019 | PMID: 31454914 |
Diagnostic mRNA splicing assay for variants in BRCA1 and BRCA2 identified two novel pathogenic splicing aberrations. | Wangensteen T | Hereditary cancer in clinical practice | 2019 | PMID: 31143303 |
Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients. | Kaur RP | Medical oncology (Northwood, London, England) | 2018 | PMID: 29700634 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. | Acedo A | Human mutation | 2015 | PMID: 25382762 |
An efficient pipeline for the generation and functional analysis of human BRCA2 variants of uncertain significance. | Hendriks G | Human mutation | 2014 | PMID: 25146914 |
BRCA1/2 and clinical outcome in a monoinstitutional cohort of women with hereditary breast cancer. | Sambiasi D | Oncology reports | 2014 | PMID: 24145998 |
Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. | Colombo M | PloS one | 2013 | PMID: 23451180 |
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 |
Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. | Finkelman BS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22430266 |
Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing. | Brandão RD | Breast cancer research and treatment | 2011 | PMID: 21638052 |
Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. | Vreeswijk MP | Human mutation | 2009 | PMID: 18693280 |
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 |
RNA-based analysis of BRCA1 and BRCA2 gene alterations. | Bonatti F | Cancer genetics and cytogenetics | 2006 | PMID: 17011978 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs80359803 ...
HelpRecord last updated May 01, 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.