ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.520C>T (p.Arg174Cys)
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.520C>T (p.Arg174Cys)
Variation ID: 51818 Accession: VCV000051818.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32326502 (GRCh38) [ NCBI UCSC ] 13: 32900639 (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 Sep 27, 2014 May 1, 2024 Nov 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.520C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg174Cys missense NC_000013.11:g.32326502C>T NC_000013.10:g.32900639C>T NG_012772.3:g.16023C>T LRG_293:g.16023C>T LRG_293t1:c.520C>T LRG_293p1:p.Arg174Cys - Protein change
- R174C
- Other names
- 748C>T
- Canonical SPDI
- NC_000013.11:32326501: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
18726 | 18884 |
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
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2023 | RCV000044608.19 | |
Uncertain significance (3) |
criteria provided, single submitter
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Nov 20, 2023 | RCV000083113.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 6, 2023 | RCV000132017.22 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2021 | RCV000217766.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 20, 2018 | RCV000779978.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV003473358.1 |
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
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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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Uncertain significance
(Feb 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Breast and Ovarian Cancer
Affected status: yes
Allele origin:
germline
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Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV001429669.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Comment:
Data included in classification: Case control comparison of UK matched against ethnically matched population data (3/25,773) in familial cases against 1/56,837 GNOMAD NFE controls pexact= … (more)
Data included in classification: Case control comparison of UK matched against ethnically matched population data (3/25,773) in familial cases against 1/56,837 GNOMAD NFE controls pexact= 0.093 (PS4_mod). Absent from the remainder of the gnomAD population (0/68,846) (PM2_mod). Assays reported by Thery 2011, Gaildrat 2012, Di Giacomo 2013 (PMID: 21673748, PMID: 22962691, PMID: 2398314) show 60-70% exon 7 skipping likely due to disruption of ESE. ESE prediction tools predict enhancer site. (PS3_mod). Variant reported in the homozygous form (1) and heterozygous form (1) on the BRCA2 Fanconi database from the Japanese Biobank. Homozygote age 60 years without personal or family history of cancer but had other complex disease (not specified). (BS2_sup). Additional data (not included in classification): The variant has also been observed in at least 2 additional UK families, 5 families tested by Ambry and is reported an additional 4 times on ClinVar. Variable segregation in UK families. None strong. Other classifications: Ambry VUS 2018; Gene Dx VUS 2017; Color VUS 2017; Invitae VUS 2017. In silico predictions mixed. (less)
Number of individuals with the variant: 3
Geographic origin: UK
Testing laboratory: UK Molecular Diagnostic Labs
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Uncertain significance
(Oct 25, 2023)
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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: SCV004211808.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jul 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000688920.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 174 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with cysteine at codon 174 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional RNA study reported this variant causes partial exon 7 skipping in minigene splicing assay and confirmed in patient RNA (PMID: 21673748). This variant has been reported in an individual affected with early-onset breast cancer and strong family history of disease (PMID: 21673748) and also in two unaffected controls in a breast cancer case-control study (PMID: 30287823). This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 03, 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: SCV000072621.10
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 174 of the BRCA2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 174 of the BRCA2 protein (p.Arg174Cys). This variant is present in population databases (rs41293469, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 21673748, 31907386). ClinVar contains an entry for this variant (Variation ID: 51818). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 04, 2022)
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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: SCV000187076.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R174C variant (also known as c.520C>T), located in coding exon 6 of the BRCA2 gene, results from a C to T substitution at nucleotide … (more)
The p.R174C variant (also known as c.520C>T), located in coding exon 6 of the BRCA2 gene, results from a C to T substitution at nucleotide position 520. The arginine at codon 174 is replaced by cysteine, an amino acid with highly dissimilar properties. Multiple splicing assays have confirmed that the BRCA2 c.520C>T induces incomplete skipping of coding exon 6-also called exon 7 in published literature (Ambry internal data; Di Giacomo D et al, Hum. Mutat. 2013 Nov; 34(11):1547-57; Gaildrat P, et al. J Med Genet. 2012;49:609-617; Théry JC, et al. Eur J Hum Genet. 2011;19:1052-1058). In addition to this exon skipping event being incomplete, the molecular and clinical impact of loss of coding exon 6 is unclear (Mesman RLS et al. Genet. Med., 2020 May). This amino acid position is well conserved in primates, however, lower organisms do not have a reference at this position on multiple sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Apr 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916956.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: BRCA2 c.520C>T (p.Arg174Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.520C>T (p.Arg174Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Though 5/5 computational tools predict no significant impact on normal splicing, one in silico study predicted potential effects by using 3 ESR-dedicated approaches (Soukarieh 2016). In vitro and in vivo studies indicated that the variant of interest induces partial exon 7 skipping (Thery 2011, Gaildrat 2012, DiGiacomo 2013). Exon 7 skipping is predicted to result in a frameshift, resulting in a truncated protein (that is subject to NMD), however, the in vivo consequence of partial exon 7 skipping is not known. Additionally, when transcribed properly, this variant results in a full length transcript with a missense alteration that could compound the in vivo consequence of this variant. The variant allele was found at a frequency of 4.1e-06 in 246130 control chromosomes. c.520C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Thery 2011, Gaildrat 2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Four 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jul 27, 2021)
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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: SCV000279421.12
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least two individuals with early-onset familial breast cancer (Thery 2011); RNA and minigene assays demonstrate partial exon 7 skipping, producing both full-length and truncated mRNA transcripts in varying proportions (Gaildrat 2012, Di Giacomo 2013). Exon 7 skipping has been reported to create a frameshift ultimately causing a premature nonsense codon, resulting in a truncated protein product that appears to undergo nonsense-mediated mRNA decay (Pyne 2000); This variant is associated with the following publications: (PMID: 32072338, 32486089, 32170000, 32123317, 30287823, 26761715, 11185744, 23983145, 22962691, 21673748) (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010359.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain Significance
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846785.1
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)
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Comment:
This missense variant replaces arginine with cysteine at codon 174 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with cysteine at codon 174 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional RNA study reported this variant causes partial exon 7 skipping in minigene splicing assay and confirmed in patient RNA (PMID: 21673748). This variant has been reported in an individual affected with early-onset breast cancer and strong family history of disease (PMID: 21673748) and also in two unaffected controls in a breast cancer case-control study (PMID: 30287823). This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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Uncertain significance
(May 01, 2012)
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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: SCV000115187.3
First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014 |
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Uncertain significance
(Sep 01, 2023)
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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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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228452.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PM2(Supporting)+PP3(Supporting)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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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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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 |
Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. | Wai HA | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32123317 |
Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer. | Kim HK | Journal of human genetics | 2020 | PMID: 31907386 |
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Clinicopathologic and Molecular Features of Colorectal Adenocarcinoma with Signet-Ring Cell Component. | Wei Q | PloS one | 2016 | PMID: 27300552 |
Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools. | Soukarieh O | PLoS genetics | 2016 | PMID: 26761715 |
Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. | Di Giacomo D | Human mutation | 2013 | PMID: 23983145 |
Evaluation of a 5-tier scheme proposed for classification of sequence variants using bioinformatic and splicing assay data: inter-reviewer variability and promotion of minimum reporting guidelines. | Walker LC | Human mutation | 2013 | PMID: 23893897 |
Multiple sequence variants of BRCA2 exon 7 alter splicing regulation. | Gaildrat P | Journal of medical genetics | 2012 | PMID: 22962691 |
Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. | Théry JC | European journal of human genetics : EJHG | 2011 | PMID: 21673748 |
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Text-mined citations for rs41293469 ...
HelpRecord last updated May 19, 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.