ClinVar Genomic variation as it relates to human health
NM_002878.4(RAD51D):c.355T>C (p.Cys119Arg)
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(9); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002878.4(RAD51D):c.355T>C (p.Cys119Arg)
Variation ID: 182856 Accession: VCV000182856.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q12 17: 35107113 (GRCh38) [ NCBI UCSC ] 17: 33434132 (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 Mar 17, 2018 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002878.4:c.355T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002869.3:p.Cys119Arg missense NM_001142571.2:c.415T>C NP_001136043.1:p.Cys139Arg missense NM_133629.3:c.145-632T>C intron variant NR_037711.2:n.381T>C non-coding transcript variant NC_000017.11:g.35107113A>G NC_000017.10:g.33434132A>G NG_031858.1:g.17757T>C LRG_516:g.17757T>C LRG_516t1:c.355T>C LRG_516p1:p.Cys119Arg - Protein change
- C119R, C139R
- Other names
- p.C119R:TGT>CGT
- Canonical SPDI
- NC_000017.11:35107112:A:G
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
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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RAD51D | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
33 | 1816 | |
RAD51L3-RFFL | - | - | - | GRCh38 | - | 1796 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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 27, 2023 | RCV000160945.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 12, 2024 | RCV000227224.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2022 | RCV000586341.11 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 9, 2024 | RCV000709444.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV001420703.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 20, 2021 | RCV001798559.4 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001354078.4 |
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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Likely benign
(Nov 17, 2015)
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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: SCV000910862.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Oct 21, 2019)
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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: SCV001470089.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Apr 16, 2021)
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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: SCV000698099.2
First in ClinVar: Mar 17, 2018 Last updated: May 21, 2021 |
Comment:
Variant summary: RAD51D c.355T>C (p.Cys119Arg) results in a non-conservative amino acid change located in the AAA+ ATPase domain of the encoded protein sequence. Three of … (more)
Variant summary: RAD51D c.355T>C (p.Cys119Arg) results in a non-conservative amino acid change located in the AAA+ ATPase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 256850 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (5.8e-05 vs 0.00013), allowing no conclusion about variant significance. c.355T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome in the absence of BRCA mutations, as well as pancreatic cancer and prostate cancer (Osher_2012, Gutierrez-Enriques_2014, Song_2015, Tung_2015, Shindo_2017, Lu_2015, Penkert_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; five classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 20, 2021)
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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: SCV002043217.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Uncertain significance
(Oct 11, 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: SCV000211652.18
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, pancreatic, and other cancers (Osher et al., 2012; Song et al., 2015; Shindo et al., 2017; Penkert et al., 2018); This variant is associated with the following publications: (PMID: 28767289, 22415235, 24130102, 26261251, 28492532, 30086788, 14704354, 19327148, 21111057, 34923718, 27535533) (less)
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Uncertain significance
(Feb 27, 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: SCV000214018.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.C119R variant (also known as c.355T>C), located in coding exon 5 of the RAD51D gene, results from a T to C substitution at nucleotide … (more)
The p.C119R variant (also known as c.355T>C), located in coding exon 5 of the RAD51D gene, results from a T to C substitution at nucleotide position 355. The cysteine at codon 119 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts (Osher DJ et al. Br. J. Cancer, 2012 Apr;106:1460-3; Gutiérrez-Enríquez S et al. Int J Cancer, 2014 May;134:2088-97; Tung N et al. Cancer, 2015 Jan;121:25-33; Song H et al. J Clin Oncol, 2015 Sep;33:2901-7; Penkert J et al. Breast Cancer Res, 2018 08;20:87). Additionally, this variant was reported in 8/60,466 breast cancer cases and in 9/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208081.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(May 03, 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: SCV002534805.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RAD51D c.355T>C (p.C119R) variant has been reported in heterozygosity in at least five individuals with breast and/or ovarian cancer or pancreatic cancer (PMID: 28767289, … (more)
The RAD51D c.355T>C (p.C119R) variant has been reported in heterozygosity in at least five individuals with breast and/or ovarian cancer or pancreatic cancer (PMID: 28767289, 22415235, 24130102, 30086788). It has also been reported in affected individuals and controls in multiple case-control studies with no significant enrichment in controls (PMID: 33471991, 26261251). It is also known as c.415A>G (p.C139R) in the literature. This variant was observed in 11/129168 chromosomes in the European (non-Finnish) population, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 182856). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
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Uncertain significance
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 4
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000287709.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 119 of the RAD51D protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 119 of the RAD51D protein (p.Cys119Arg). This variant is present in population databases (rs201313861, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic ductal adenocarcinoma (PMID: 22415235, 24130102, 25186627, 26261251, 28767289, 30086788). This variant is also known as c.415A>G (p.C139R). ClinVar contains an entry for this variant (Variation ID: 182856). 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 RAD51D protein function with a negative predictive value of 80%. 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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Likely benign
(Apr 09, 2024)
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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:
unknown
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Mendelics
Accession: SCV000839188.3
First in ClinVar: Oct 10, 2018 Last updated: Apr 15, 2024 |
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Uncertain significance
(Jul 31, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550924.7
First in ClinVar: Jul 28, 2022 Last updated: Aug 04, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548605.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The RAD51D p.Cys119Arg variant was identified in 4 of 8892 proband chromosomes (frequency: 0.0004) from individuals or families with breast and ovarian cancer and was … (more)
The RAD51D p.Cys119Arg variant was identified in 4 of 8892 proband chromosomes (frequency: 0.0004) from individuals or families with breast and ovarian cancer and was present in 2 of 5544 control chromosomes (frequency: 0.0004) from healthy individuals (Gutierrez-Enriquez 2013, Osher 2012, Song 2015). The variant was also identified in dbSNP (ID: rs201313861) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by GeneDx, Ambry genetics, Invitae, LCOA clinical laboratory). The variant was not identified in the Cosmic database. The variant was identified in control databases in 15 of 277134 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Latino in 3 of 34420 chromosomes (freq: 0.0001), European in 11 of 126692 chromosomes (freq: 0.0001); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys119 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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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 |
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity. | Penkert J | Breast cancer research : BCR | 2018 | PMID: 30086788 |
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. | Shindo K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28767289 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. | Song H | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 26261251 |
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 |
About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants. | Gutiérrez-Enríquez S | International journal of cancer | 2014 | PMID: 24130102 |
Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. | Osher DJ | British journal of cancer | 2012 | PMID: 22415235 |
Text-mined citations for rs201313861 ...
HelpRecord last updated Sep 29, 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.