ClinVar Genomic variation as it relates to human health
NM_058216.3(RAD51C):c.640C>T (p.Arg214Cys)
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.
Uncertain significance(7); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_058216.3(RAD51C):c.640C>T (p.Arg214Cys)
Variation ID: 141324 Accession: VCV000141324.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q22 17: 58703264 (GRCh38) [ NCBI UCSC ] 17: 56780625 (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 Dec 19, 2017 May 12, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_058216.3:c.640C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478123.1:p.Arg214Cys missense NM_058217.1:c.*68C>T NR_103872.2:n.515C>T non-coding transcript variant NC_000017.11:g.58703264C>T NC_000017.10:g.56780625C>T NG_023199.1:g.15663C>T NG_156533.1:g.140C>T LRG_314:g.15663C>T LRG_314t1:c.640C>T LRG_314p1:p.Arg214Cys - Protein change
- R214C
- Other names
- p.R214C:CGT>TGT
- Canonical SPDI
- NC_000017.11:58703263: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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00017
Trans-Omics for Precision Medicine (TOPMed) 0.00020
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RAD51C | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1818 | 2026 | |
LOC129390903 | - | - | - | GRCh38 | - | 160 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 2, 2023 | RCV000129799.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000204512.20 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2023 | RCV000212945.18 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 26, 2024 | RCV000781795.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 13, 2017 | RCV000662365.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 1, 2022 | RCV003492593.1 | |
Benign (1) |
criteria provided, single submitter
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Jan 1, 2022 | RCV003153419.9 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 5, 2023 | RCV003315883.8 |
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
(Dec 10, 2022)
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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: SCV000211616.17
First in ClinVar: Feb 24, 2015 Last updated: Dec 24, 2022 |
Comment:
Published functional studies are inconclusive: demonstrates reduced binding with XRCC3 and RAD51B in one study, while another study showed RAD51D, RAD51B and XRCC3 binding similar … (more)
Published functional studies are inconclusive: demonstrates reduced binding with XRCC3 and RAD51B in one study, while another study showed RAD51D, RAD51B and XRCC3 binding similar to wild-type and proficient homologous recombination (HR) activity (Clague et al., 2011; Prakash et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23117857, 25186627, 25470109, 21980511, 27443514, 28829762, 30093976, 14704354, 36099300) (less)
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Uncertain significance
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group O
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000261245.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 214 of the RAD51C protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 214 of the RAD51C protein (p.Arg214Cys). This variant is present in population databases (rs140804406, gnomAD 0.06%). This missense change has been observed in individual(s) with breast, ovarian or endometrial cancer (PMID: 21980511, 25186627, 27443514, 30093976). ClinVar contains an entry for this variant (Variation ID: 141324). 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 RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 21980511). 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
(Nov 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group O
Breast-ovarian cancer, familial, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000784752.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Likely benign
(Jan 05, 2016)
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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: SCV000903132.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Jun 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070774.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(May 18, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530000.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RAD51C c.640C>T (p.R214C) variant has been reported in several individuals with breast, ovarian, or endometrial cancers (PMID: 33471991, 25186627, 21980511, 30093976, 27443514), and was … (more)
The RAD51C c.640C>T (p.R214C) variant has been reported in several individuals with breast, ovarian, or endometrial cancers (PMID: 33471991, 25186627, 21980511, 30093976, 27443514), and was also reported in healthy controls (PMID: 33471991). It was observed in 17/24962 chromosomes of the African/African American subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 141324). In silico tools suggest the impact of the variant on protein function is benign. Yeast two-hybrid based assay showed a small but significant decrease in interaction of the mutant RAD51C protein with XRCC3 and RAD51B, but did not find any changes to the steady-state levels of RAD51C (PMID: 21980511). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Benign
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ovarian cancer
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Accession: SCV003843275.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
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Likely benign
(Apr 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019913.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(Jun 26, 2023)
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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: SCV001134789.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21980511 (2011), 25186627 (2015), (30093976 (2018), 33471991 (2021)), … (more)
In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21980511 (2011), 25186627 (2015), (30093976 (2018), 33471991 (2021)), in an individua with endometrial cancer (PMID: 27443514 (2016)) as well as in unaffected controls (PMID: 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/ RAD51C)). In a yeast-two-hybrid assay, the variant resulted in reduced RAD51C protein level and binding with XRCC3 and RAD51B (PMID 21980511 (2011)). However, more recent studies using both cell-based homologous recombination (HR) assays and yeast analysis showed that the variant retained normal binding to RAD51D, RAD51B and XRCC3, and had proficient HR activity (PMIDs: 36099300 (2022) and 37253112 (2023)). The frequency of this variant in the general population, 0.00068 (17/24962 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239992.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Feb 02, 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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Ambry Genetics
Accession: SCV000184609.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Mar 26, 2024)
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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: SCV000920122.3
First in ClinVar: Jun 02, 2019 Last updated: May 12, 2024 |
Comment:
Variant summary: SDHB c.640C>T (p.Gln214X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SDHB c.640C>T (p.Gln214X) 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. The variant was absent in 251290 control chromosomes. c.640C>T has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Reusch_2007, Kim_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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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Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C. | Hu C | Cancer research | 2023 | PMID: 37253112 |
Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants. | Prakash R | Proceedings of the National Academy of Sciences of the United States of America | 2022 | PMID: 36099300 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
Genetic testing for RAD51C mutations: in the clinic and community. | Sopik V | Clinical genetics | 2015 | PMID: 25470109 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Germline mutations in RAD51C in Jewish high cancer risk families. | Kushnir A | Breast cancer research and treatment | 2012 | PMID: 23117857 |
RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. | Clague J | PloS one | 2011 | PMID: 21980511 |
Text-mined citations for rs140804406 ...
HelpRecord last updated Jun 10, 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.