ClinVar Genomic variation as it relates to human health
NM_002878.4(RAD51D):c.349T>A (p.Cys117Ser)
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.349T>A (p.Cys117Ser)
Variation ID: 184247 Accession: VCV000184247.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q12 17: 35107119 (GRCh38) [ NCBI UCSC ] 17: 33434138 (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 Jan 6, 2017 Jul 15, 2024 Apr 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002878.4:c.349T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002869.3:p.Cys117Ser missense NM_001142571.2:c.409T>A NP_001136043.1:p.Cys137Ser missense NM_133629.3:c.145-638T>A intron variant NR_037711.2:n.375T>A non-coding transcript variant NC_000017.11:g.35107119A>T NC_000017.10:g.33434138A>T NG_031858.1:g.17751T>A LRG_516:g.17751T>A LRG_516t1:c.349T>A LRG_516p1:p.Cys117Ser - Protein change
- C117S, C137S
- Other names
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- Canonical SPDI
- NC_000017.11:35107118:A: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.
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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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 9, 2024 | RCV000163461.15 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000410914.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 26, 2023 | RCV000478670.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 24, 2024 | RCV004586583.1 |
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
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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
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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 26, 2023)
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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: SCV000565464.5
First in ClinVar: Apr 29, 2017 Last updated: Nov 11, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual with ovarian cancer and one individual with breast cancer (Song et al., 2015; Tung et al., 2015); This variant is associated with the following publications: (PMID: 26261251, 25186627, 21111057, 14704354, 19327148) (less)
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Uncertain significance
(Apr 06, 2023)
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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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Myriad Genetics, Inc.
Accession: SCV004017721.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Dec 06, 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: SCV000686447.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces cysteine with serine at codon 117 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces cysteine with serine at codon 117 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer or ovarian cancer (PMID: 25186627, 26261251). This variant has not been identified 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
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000214012.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.C117S variant (also known as c.349T>A), located in coding exon 5 of the RAD51D gene, results from a T to A substitution at nucleotide … (more)
The p.C117S variant (also known as c.349T>A), located in coding exon 5 of the RAD51D gene, results from a T to A substitution at nucleotide position 349. The cysteine at codon 117 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was detected in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This alteration has also been detected in 1/1781 individuals with a breast cancer diagnosis (Tung N. Cancer. 2015 Jan;121(1):25-33). In addition, this alteration was reported in 4/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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
(Mar 25, 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: SCV004200369.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Mar 01, 2022)
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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: SCV002534804.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RAD51D c.349T>A (p.C117S) variant has been reported in heterozygosity in one individual with breast cancer and one individual with ovarian cancer (PMID: 25186627, 26261251). … (more)
The RAD51D c.349T>A (p.C117S) variant has been reported in heterozygosity in one individual with breast cancer and one individual with ovarian cancer (PMID: 25186627, 26261251). It has been reported in a large case-control study of breast cancer in 4/60466 cases and in 2/53461 controls (PMID: 33471991). This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 184247). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. 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
(Aug 22, 2016)
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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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Counsyl
Accession: SCV000489115.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Jan 20, 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: SCV000551381.10
First in ClinVar: Jan 06, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 117 of the RAD51D protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 117 of the RAD51D protein (p.Cys117Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25186627, 26261251). ClinVar contains an entry for this variant (Variation ID: 184247). 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%. 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
(Apr 24, 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: SCV005076611.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: RAD51D c.349T>A (p.Cys117Ser) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal (IPR003593) of the … (more)
Variant summary: RAD51D c.349T>A (p.Cys117Ser) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.349T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Tung_2015, Song_2015). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 26261251, 25186627). ClinVar contains an entry for this variant (Variation ID: 184247). Based on the evidence outlined above, the variant was classified as 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 |
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 |
Text-mined citations for rs786201358 ...
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.