ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.67+2T>C
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+2T>C
Variation ID: 52163 Accession: VCV000052163.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32316529 (GRCh38) [ NCBI UCSC ] 13: 32890666 (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 Apr 20, 2024 Jun 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.67+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001406719.1:c.67+2T>C splice donor NM_001406720.1:c.67+2T>C splice donor NM_001406721.1:c.67+2T>C splice donor NM_001406722.1:c.-303+862T>C intron variant NC_000013.11:g.32316529T>C NC_000013.10:g.32890666T>C NG_012772.3:g.6050T>C NG_017006.2:g.3835A>G LRG_293:g.6050T>C LRG_293t1:c.67+2T>C U43746.1:n.295+2T>C - Protein change
- Other names
- IVS2+2T>C
- Canonical SPDI
- NC_000013.11:32316528:T:C
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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 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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May 30, 2023 | RCV000045024.19 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2023 | RCV000113081.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 22, 2023 | RCV000985570.15 |
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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Pathogenic
(Jan 01, 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: yes
Allele origin:
germline
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Genologica Medica
Additional submitter:
Servicio Andaluz de Salud, Hospital Universitario Virgen de la Victoria
Accession: SCV000577942.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Family history: yes
Ethnicity/Population group: Causasians
Geographic origin: Spain
Tissue: Blood
Secondary finding: no
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Pathogenic
(Oct 11, 2018)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133872.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 03, 2022 |
Comment:
The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and … (more)
The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. (less)
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Pathogenic
(Oct 04, 2017)
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criteria provided, single submitter
Method: provider interpretation, clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
paternal
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Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804388.2
First in ClinVar: Apr 01, 2014 Last updated: Dec 11, 2022 |
Comment:
This variant was identified in a 3 year old male with autism spectrum disorder, global developmental delay, hypotonia, and plagiocephaly, as a secondary finding. It … (more)
This variant was identified in a 3 year old male with autism spectrum disorder, global developmental delay, hypotonia, and plagiocephaly, as a secondary finding. It was inherited from a healthy father who's family history includes several females with breast cancer. This variant has been reported in the literature and in ClinVar as a pathogenic variant, due to association with hereditary breast/ovarian cancer. The variant alters a canonical splice site. (less)
Observation 1:
Clinical Features:
Autistic disorder of childhood onset (present) , Global developmental delay (present) , Muscular hypotonia (present) , Plagiocephaly (present)
Age: 0-9 years
Sex: male
Secondary finding: yes
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-09-05
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autistic disorder of childhood onset (present) , Global developmental delay (present) , Muscular hypotonia (present) , Plagiocephaly (present)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-09-05
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Oct 27, 2016)
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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: SCV000489568.2
First in ClinVar: Apr 01, 2014 Last updated: Dec 24, 2022 |
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Pathogenic
(May 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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Invitae
Accession: SCV000073037.9
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17011978, 22505045, 30883759). ClinVar contains an entry for this variant (Variation ID: 52163). This variant is also known as IVS2+2T>C and 295+2T>C. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer and/or breast cancer (PMID: 12955716, 21063910, 22798144). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs81002885, gnomAD 0.0009%). 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. (less)
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Pathogenic
(Nov 03, 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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848792.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.67+2T>C variant in BRCA2 has been reported in at least 7 individuals affected with Hereditary Breast and Ovarian Cancer (selected references, Diez 2003 PMID: … (more)
The c.67+2T>C variant in BRCA2 has been reported in at least 7 individuals affected with Hereditary Breast and Ovarian Cancer (selected references, Diez 2003 PMID: 12955716, Al Hannan 2019 PMID: 31131559, Rebbeck 2018 PMID: 29446198, Pajares 2018 PMID: 29884136). It has also been reported in ClinVar (Variation ID 52163) but was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that this variant affects mRNA splicing (Houdayer 2012 PMID: 22505045, Fraile-Bethencourt 2019 PMID: 30883759). Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PM2_supporting, PVS1, PS4_Moderate. (less)
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Pathogenic
(Jan 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001337839.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: BRCA2 c.67+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: BRCA2 c.67+2T>C is 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: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Houdayer_2012). The variant allele was found at a frequency of 4e-06 in 250582 control chromosomes. c.67+2T>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Diez_2003, AlHannan_2019, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories and one 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
(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: SCV000327503.4
First in ClinVar: Apr 01, 2014 Last updated: Dec 11, 2022 |
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Pathogenic
(Jun 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003932750.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
A known pathogenic mutation was detected in the BRCA2 gene (c.67+2T>C). This sequence change affects a donor splice site in intron 2 of the BRCA2 … (more)
A known pathogenic mutation was detected in the BRCA2 gene (c.67+2T>C). This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (gnomAD). This variant has been reported in an individual and a family affected with breast/ovarian cancer (PMID: 12955716, 22798144). This variant is also known as IVS2+2T>C and 295+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 52163). Experimental studies have shown that this intronic change disrupts splicing and results in an mRNA product with exon 2 skipped (PMID: 22505045). Exon 2 contains the translational start site of BRCA2. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing . (less)
Sex: female
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Pathogenic
(Jun 22, 2023)
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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: SCV001773614.4
First in ClinVar: Aug 07, 2021 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: results in exon 2 skipping which contains the initiator codon, unable to rescue cell viability in a complementation … (more)
Published functional studies demonstrate a damaging effect: results in exon 2 skipping which contains the initiator codon, unable to rescue cell viability in a complementation assay (Houdayer et al., 2012; Fraile-Bethencourt et al., 2019; Mesman et al., 2020); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Diez et al., 2003; Martinez-Ferrandis et al., 2003; Kim et al., 2012; Pajares et al., 2018; Al Hannan et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 295+2T>C; This variant is associated with the following publications: (PMID: 31131967, 29446198, 31131559, 14517958, 25525159, 22798144, 22505045, 12955716, 18528753, 30720243, 29884136, 33654310, 32398771, 30883759) (less)
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Pathogenic
(Feb 20, 2004)
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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: SCV000146096.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Geographic origin: Latin American, Caribbean, Western European
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
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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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Characterization of BRCA1 and BRCA2 genetic variants in a cohort of Bahraini breast cancer patients using next-generation sequencing. | Al Hannan F | Molecular genetics & genomic medicine | 2019 | PMID: 31131559 |
Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays. | Fraile-Bethencourt E | The Journal of pathology | 2019 | PMID: 30883759 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. | Kim H | Breast cancer research and treatment | 2012 | PMID: 22798144 |
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 |
Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. | Díez O | Human mutation | 2003 | PMID: 12955716 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs81002885 ...
HelpRecord last updated Apr 20, 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.