17-35101311-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting
The NM_002878.4(RAD51D):c.793G>A(p.Gly265Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000682 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 0 hom. )
Consequence
RAD51D
NM_002878.4 missense
NM_002878.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 5.74
Genes affected
RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RAD51D | ENST00000345365.11 | c.793G>A | p.Gly265Arg | missense_variant | Exon 9 of 10 | 1 | NM_002878.4 | ENSP00000338790.6 | ||
| ENSG00000267618 | ENST00000593039.5 | c.316G>A | p.Gly106Arg | missense_variant | Exon 5 of 7 | 2 | ENSP00000466834.1 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152120Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
5
AN:
152120
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251418Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135884
GnomAD3 exomes
AF:
AC:
12
AN:
251418
Hom.:
AF XY:
AC XY:
6
AN XY:
135884
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000718 AC: 105AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727228
GnomAD4 exome
AF:
AC:
105
AN:
1461862
Hom.:
Cov.:
31
AF XY:
AC XY:
43
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000329 AC: 5AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74314
GnomAD4 genome
AF:
AC:
5
AN:
152120
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74314
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
5
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 20, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22415235, 21822267, 26261251, 23372765, 29255180, 32986223, 33471991, 34923718, 35264596, 21111057, 14704354, 19327148) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 29, 2024 | The RAD51D c.793G>A (p.Gly265Arg) variant (also known as c.853G>A (p.Gly285Arg) in the NM_001142571.1 transcript) has been reported in the published literature in individuals with personal or family history of breast/ovarian cancer (PMIDs: 35264596 (2022), 32986223 (2021), 32068069 (2020), 29255180 (2017), 26328243 (2015), 23372765 (2013), 22415235 (2012)). It has also been identified in reportedly healthy individuals (PMIDs: 26261251 (2015), 21822267 (2011)), and described to not segregate with disease in a breast/ovarian cancer family (PMID: 22415235 (2012)). This variant was observed in additional breast cancer cases as well as in reportedly healthy individuals in a large case-control study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000062 (8/129160 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 08, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 01, 2024 | The missense variant NM_002878.4(RAD51D):c.793G>A (p.Gly265Arg) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gly265Arg variant is observed in 8/113,740 (0.007%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Gly265Arg variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between glycine and arginine. The p.Gly265Arg missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 265 of RAD51D is conserved in all mammalian species. The nucleotide c.793 in RAD51D is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2023 | The p.G265R variant (also known as c.793G>A), located in coding exon 9 of the RAD51D gene, results from a G to A substitution at nucleotide position 793. The glycine at codon 265 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in BRCA1/2-negative individuals with personal and/or family history suggestive of familial breast and ovarian cancer (Osher DJ et al. Br. J. Cancer 2012 Apr;106:1460-3; Thompson ER et al. PLoS ONE 2013;8(1):e54772). However, in one study this variant did not segregate with the disease in a carrier family leading authors to conclude it was most likely benign (Osher DJ et al. Br. J. Cancer 2012 Apr;106:1460-3). Further, this alteration has also been reported in healthy control populations (Loveday C et al. Nat. Genet. 2011 Aug;43:879-82; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 26, 2022 | This missense variant replaces glycine with arginine at codon 265 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 reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 23372765), as well as in three unaffected control individuals in case-control studies (PMID: 26261251, 21822267). This variant has been reported to not segregate with disease in a family affected with breast and ovarian cancer (PMID: 22415235). In a large cancer case-control study, this variant has not shown significant association with breast cancer (11/60455 cases, 17/53444 controls; OR=0.572; 95%CI 0.268 to 1.221; p-value=0.185; Leiden Open Variation Database DB-ID RAD51D_000037) (PMID: 33471991). This variant has been identified in 12/246190 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. - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 04, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 265 of the RAD51D protein (p.Gly265Arg). This variant is present in population databases (rs140285068, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 22415235, 23372765, 35264596). This variant is also known as c.853G>A (p.Gly285Arg). ClinVar contains an entry for this variant (Variation ID: 142125). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RAD51D protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 01, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;T;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;.;H;H;.;.;.
PROVEAN
Pathogenic
.;.;.;D;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;D;.;.;.;.
Sift4G
Benign
T;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;D;D;D;.;.
Vest4
MutPred
0.92
.;.;.;Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at