ClinVar Genomic variation as it relates to human health
NM_002878.4(RAD51D):c.434G>A (p.Arg145His)
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_002878.4(RAD51D):c.434G>A (p.Arg145His)
Variation ID: 187149 Accession: VCV000187149.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q12 17: 35107034 (GRCh38) [ NCBI UCSC ] 17: 33434053 (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 Feb 19, 2018 Oct 8, 2024 Mar 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002878.4:c.434G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002869.3:p.Arg145His missense NM_001142571.2:c.494G>A NP_001136043.1:p.Arg165His missense NM_133629.3:c.145-553G>A intron variant NR_037711.2:n.460G>A non-coding transcript variant NC_000017.11:g.35107034C>T NC_000017.10:g.33434053C>T NG_031858.1:g.17836G>A LRG_516:g.17836G>A LRG_516t1:c.434G>A LRG_516p1:p.Arg145His - Protein change
- R145H, R165H
- Other names
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- Canonical SPDI
- NC_000017.11:35107033: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 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00019
The Genome Aggregation Database (gnomAD) 0.00023
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
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2023 | RCV000166844.14 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 24, 2024 | RCV000469434.13 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2024 | RCV000590143.8 | |
RAD51D-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Dec 19, 2023 | RCV003937516.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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
(Jan 04, 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: SCV000217658.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R145H variant (also known as c.434G>A), located in coding exon 5 of the RAD51D gene, results from a G to A substitution at nucleotide … (more)
The p.R145H variant (also known as c.434G>A), located in coding exon 5 of the RAD51D gene, results from a G to A substitution at nucleotide position 434. The arginine at codon 145 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
(Dec 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698104.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The RAD51D c.434G>A (p.Arg145His) variant located in the P-loop containing nucleoside triphosphate hydrolase and C-terminal domain (via InterPro) causes a missense change involving … (more)
Variant summary: The RAD51D c.434G>A (p.Arg145His) variant located in the P-loop containing nucleoside triphosphate hydrolase and C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 6/121410 (1/20242), which does not exceed the estimated maximal expected allele frequency for a pathogenic RAD51D variant of 1/8000. One clinical diagnostic laboratory has classified this variant as uncertain significance. The variant of interest has been reported in at least one patient sample referred for NGS-based multigene hereditary-cancer testing without strong evidence for causality (Mu_2016). Taken together, the variant is classified as a variant of uncertain significance (VUS), until additional information becomes available. (less)
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Uncertain significance
(Mar 24, 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: SCV004208080.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Dec 27, 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: SCV001470632.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Jun 15, 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: SCV002534817.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RAD51D c.434G>A (p.R145H) variant has been reported in at least 3 individuals with breast cancer but has also been reported in a healthy control … (more)
The RAD51D c.434G>A (p.R145H) variant has been reported in at least 3 individuals with breast cancer but has also been reported in a healthy control individual (PMID: 30111881, 33471991). It was observed in 14/24952 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 187149). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. 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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Uncertain significance
(Jun 21, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000686456.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 145 of the RAD51D protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with histidine at codon 145 of the RAD51D protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 30111881). In a large breast cancer case-control study, this variant was identified in 2/60464 cases and 1/53460 controls - OR=1.768 (95%CI 0.16 to 19.503); p-value=1 (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000140). This variant has also been identified in 16/282828 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
(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: SCV000551361.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 145 of the RAD51D protein (p.Arg145His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 145 of the RAD51D protein (p.Arg145His). This variant is present in population databases (rs147264215, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with RAD51D-related disease (PMID: 30111881). ClinVar contains an entry for this variant (Variation ID: 187149). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51D protein function. 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
(Feb 16, 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: SCV000565465.8
First in ClinVar: Apr 29, 2017 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or prostate cancer, as well … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or prostate cancer, as well as in both cases and controls from a breast cancer study (PMID: 30111881, 32832836, 33471991); This variant is associated with the following publications: (PMID: 26057125, 27720647, 30111881, 33471991, 32832836, 21111057, 14704354, 19327148) (less)
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Uncertain significance
(Mar 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000859941.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Dec 18, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782214.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Dec 19, 2023)
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no assertion criteria provided
Method: clinical testing
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RAD51D-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004766250.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The RAD51D c.434G>A variant is predicted to result in the amino acid substitution p.Arg145His. This variant has been reported as uncertain in a study of … (more)
The RAD51D c.434G>A variant is predicted to result in the amino acid substitution p.Arg145His. This variant has been reported as uncertain in a study of Greek patients with breast and ovarian cancer (Konstanta et al. 2018. PubMed ID: 30111881). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/187149/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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 |
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. | Matejcic M | JCO precision oncology | 2020 | PMID: 32832836 |
Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece. | Konstanta I | Journal of human genetics | 2018 | PMID: 30111881 |
Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. | Mu W | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27720647 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RAD51D | - | - | - | - |
Text-mined citations for rs147264215 ...
HelpRecord last updated Oct 08, 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.