ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.250C>T (p.Gln84Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.250C>T (p.Gln84Ter)
Variation ID: 51298 Accession: VCV000051298.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32319259 (GRCh38) [ NCBI UCSC ] 13: 32893396 (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 Oct 8, 2024 Apr 22, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.250C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gln84Ter nonsense NC_000013.11:g.32319259C>T NC_000013.10:g.32893396C>T NG_012772.3:g.8780C>T NG_017006.2:g.1105G>A LRG_293:g.8780C>T LRG_293t1:c.250C>T LRG_293p1:p.Gln84Ter U43746.1:n.478C>T - Protein change
- Q84*
- Other names
- p.Q84*:CAA>TAA
- 478C>T
- Canonical SPDI
- NC_000013.11:32319258:C:T
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Jun 12, 2024 | RCV000044007.19 | |
Pathogenic (5) |
reviewed by expert panel
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Apr 22, 2016 | RCV000077281.17 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2023 | RCV000195353.20 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 13, 2024 | RCV000564855.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 30, 2021 | RCV003473315.1 | |
Pathogenic (1) |
no assertion criteria provided
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May 6, 2024 | RCV004724776.1 |
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. |
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Pathogenic
(Apr 22, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000282368.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Aug 02, 2021)
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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: SCV001774610.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Variant summary: BRCA2 c.250C>T (p.Gln84X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.250C>T (p.Gln84X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251326 control chromosomes. c.250C>T 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. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All sumbitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 02, 2019)
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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: SCV004847696.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gln84X variant in BRCA2 has been reported in >10 individuals with BRCA2-related cancers, as well as in one man with prostate cancer (Willems 2008, … (more)
The p.Gln84X variant in BRCA2 has been reported in >10 individuals with BRCA2-related cancers, as well as in one man with prostate cancer (Willems 2008, Turkovic 2010, Kwong 2012, Lang 2017, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 84, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In addition, this variant was classified as Pathogenic by the ClinGen-approved ENIGMA expert panel (Variation ID: 51298). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. (less)
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Pathogenic
(Jun 12, 2024)
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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: SCV000210438.14
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 20807450, 21939546, 22970155, 28294317); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 478C>T; This variant is associated with the following publications: (PMID: 18445692, 26586665, 20858050, 26681312, 28294317, 29446198, 30702160, 20807450, 21939546, 22970155, 34399810, 30720863, 31825140, 31090900, 30787465, 20104584, 34887416, 37310942, 30145549, 31853058, 35216584) (less)
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Pathogenic
(Oct 30, 2021)
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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: SCV004212889.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 13, 2024)
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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: SCV000665934.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.Q84* pathogenic mutation (also known as c.250C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at … (more)
The p.Q84* pathogenic mutation (also known as c.250C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 250. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been reported in multiple individuals and families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Willems AJ et al. Clin. Cancer Res., 2008 May;14:2953-61; Turkovic L et al. BMC Cancer, 2010;10:466; Coulet F et al. Genet Test Mol Biomarkers, 2010 Oct;14:677-90; Muller D et al. BMC Med. Genet., 2011 Sep;12:121; Kwong A et al. PLoS ONE, 2012 Sep;7:e43994; Susswein LR et al. Genet Med, 2016 08;18:823-32; Lang GT et al. Int J Cancer, 2017 07;141:129-142; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Nones K et al. Ann Oncol, 2019 07;30:1071-1079). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 04, 2020)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000903712.3
First in ClinVar: May 19, 2019 Last updated: Jan 15, 2022 |
Comment:
This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals at high-risk for breast and/or ovarian cancer (PMID: 21939546, 22970155) and in an individual affected with prostate cancer from a family with multiple cases of breast cancer (PMID: 18445692). 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)
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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: SCV000326715.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jan 19, 2021)
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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: SCV000296646.5
First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024 |
Comment:
his nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in families affected with prostate cancer or breast/ovarian … (more)
his nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in families affected with prostate cancer or breast/ovarian cancer in the published literature (PMID: 18445692 (2008), 21939546 (2011), 29446198 (2018), 30702160 (2019)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 10, 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: SCV000072020.11
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln84*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln84*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian and prostate cancer (PMID: 18445692, 20807450, 20858050, 21939546, 22970155). This variant is also known as 478C>T. ClinVar contains an entry for this variant (Variation ID: 51298). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 18, 2011)
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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: SCV000109078.3
First in ClinVar: Dec 23, 2013 Last updated: Jun 24, 2016 |
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Pathogenic
(May 06, 2024)
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no assertion criteria provided
Method: clinical testing
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BRCA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005338598.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The BRCA2 c.250C>T variant is predicted to result in premature protein termination (p.Gln84*). This variant is also referred to as c.478C>T in literature. It has … (more)
The BRCA2 c.250C>T variant is predicted to result in premature protein termination (p.Gln84*). This variant is also referred to as c.478C>T in literature. It has been reported in several individuals with breast or prostate cancer (see for example, Willems et al. 2008. PubMed ID: 18445692; Table S3, Lang et al. 2017. PubMed ID: 28294317; Table 2, Murali et al. 2021. PubMed ID: 34399810). It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51298/). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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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: SCV000587543.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(Mar 02, 2020)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV004243692.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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not provided
(-)
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no classification provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline,
somatic
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146448.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 3
Ethnicity/Population group: Western European
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Angolan
Geographic origin: English
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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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Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. | Nones K | Annals of oncology : official journal of the European Society for Medical Oncology | 2019 | PMID: 31090900 |
Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. | Deng M | International journal of cancer | 2019 | PMID: 30720863 |
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. | Bhaskaran SP | International journal of cancer | 2019 | PMID: 30702160 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations? | Nguyen-Dumont T | BMC cancer | 2018 | PMID: 29422015 |
The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing. | Lang GT | International journal of cancer | 2017 | PMID: 28294317 |
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 |
Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. | Kwong A | PloS one | 2012 | PMID: 22970155 |
An entire exon 3 germ-line rearrangement in the BRCA2 gene: pathogenic relevance of exon 3 deletion in breast cancer predisposition. | Muller D | BMC medical genetics | 2011 | PMID: 21939546 |
A one-step prescreening for point mutations and large rearrangement in BRCA1 and BRCA2 genes using quantitative polymerase chain reaction and high-resolution melting curve analysis. | Coulet F | Genetic testing and molecular biomarkers | 2010 | PMID: 20858050 |
Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age. | Turkovic L | BMC cancer | 2010 | PMID: 20807450 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. | Willems AJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18445692 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
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Text-mined citations for rs80358515 ...
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.