Submissions for variant NM_002878.4(RAD51D):c.796C>T (p.Arg266Cys)

gnomAD frequency: 0.00005  dbSNP: rs587781813

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130084	SCV000184912	likely benign	Hereditary cancer-predisposing syndrome	2022-09-20	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000255993	SCV000321930	uncertain significance	not provided	2025-03-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and/or ovarian cancer, but also in unaffected controls (PMID: 23372765, 29522266, 30111881, 29470806, 30651582, 31159747, 33471991); This variant is associated with the following publications: (PMID: 30651582, 23372765, 25775023, 29522266, 30111881, 31159747, 29470806, 36690744, 33471991, 26689913, 34284872, 36495689, 38909640, 36243179, 21111057, 14704354, 19327148, 35988656)
Counsyl	RCV000411407	SCV000489353	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-09-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411407	SCV000551380	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130084	SCV000686488	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 266 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 23372765, 29470806, 29522266, 30111881, 30651582). In a large breast cancer case-control study, this variant was identified in 6/60466 cases and 2/53461 controls (OR=2.653, 95%CI 0.535 to 13.143; p-value=0.296; PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000013). This variant has also been identified in 46/282806 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.
GeneKor MSA	RCV000130084	SCV000822184	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255993	SCV000888611	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The RAD51D c.796C>T (p.Arg266Cys) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared), 30651582 (2019), 30111881 (2018), 29522266 (2018), 29470806 (2018), 23372765 (2013)), soft tissue sarcoma (PMID: 35988656 (2022)) as well as in reportedly healthy individuals (PMID: 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.00085 (26/30616 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000411407	SCV001140411	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193713	SCV001362752	likely benign	not specified	2024-04-10	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.796C>T (p.Arg266Cys) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 1614150 control chromosomes, predominantly at a frequency of 0.00081 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.48 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.796C>T, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Thompson_2013, Lu_2015, Konstanta_2018, Krivokuca_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. 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: 30111881, 30651582, 26689913, 23372765). ClinVar contains an entry for this variant (Variation ID: 141519). Based on the evidence outlined above, the variant was classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000411407	SCV001440342	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255993	SCV001446447	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000255993	SCV002010050	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130084	SCV002534857	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000411407	SCV002556931	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2020-10-07	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000411407	SCV002581666	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2022-08-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411407	SCV004017728	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193713	SCV004026732	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483498	SCV004228254	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-11	criteria provided, single submitter	curation	Contradictory data: In GC-HBOC centers also frequently found in non HBOC cases. In Cologne found 16X in 27.000 HBOC cases. In gnomAD found 16X in 75.000 NFEs and 26X in 15.000 SAS. Own functional analysis (unpublished) revealed damaging effect and LOH and Segregation in a family In Dorling et al. found 6X in 60466 BC cases and 2X in 53461 nonBC controls. According to the ACMG standard criteria we chose these criteria: PS3 (supporting pathogenic): Own functional analysis (unpublished) revealed damaging effect and LOH and Segregation in a family, BS1 (supporting benign): contradictory data: In GC-HBOC centers also frequently found in non HBOC cases. In Cologne found 16X in 27.000 HBOC cases. In gnomAD found 16X in 75.000 NFEs and 26X in 15.000 SAS. In Dorling et al. found 6X in 60466 BC cases and 2X in 53461 nonBC controls.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492595	SCV004240004	uncertain significance	Breast and/or ovarian cancer	2023-06-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000411407	SCV005042644	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4		criteria provided, single submitter	clinical testing	The missense c.796C>T p.Arg266Cys variant in the RAD51D gene has been reported has been reported in individuals affected with breast and ovarian cancer Hauke, Jan et al., 2018. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Likely Benign/ Uncertain Significance multiple submissions. The amino acid Arginine at position 266 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg266Cys in RAD51D is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000411407	SCV005640001	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-06-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891666	SCV000806588	uncertain significance	RAD51D-related disorder	2024-02-11	no assertion criteria provided	clinical testing	The RAD51D c.796C>T variant is predicted to result in the amino acid substitution p.Arg266Cys. This variant has been reported in individuals with ovarian and/or breast cancer, but the clinical significance is unknown (Thompson et al. 2013. PubMed ID: 23372765; Konstanta et al. 2018. PubMed ID: 30111881; Supplementary Table S5 in Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.085% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain significance by the vast majority of clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141519/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect, ClinGen	RCV002508924	SCV000986823	not provided	Hereditary site-specific ovarian cancer syndrome		no assertion provided	phenotyping only	Variant identified in multiple GenomeConnect participants. Variant classified as Uncertain significance and reported, most recently, on 11-27-2021 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357548	SCV001553048	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	RAD51D, EXON9, c.796C>T, p.Arg266Cys, Heterozygous, Uncertain Significance The RAD51D p.Arg266Cys variant was identified in 3 of 16,144 proband chromosomes (frequency: 0.0002) from individuals with breast or ovarian cancer and was not identified in 5310 control chromosomes from healthy individuals (Thompson 2013, Konstanta 2018, Hauke 2018). The variant was identified in dbSNP (rs587781813) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and 6 other submitters). The variant was identified in control databases in 42 of 277,160 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24,030 chromosomes (freq: 0.00008), Other in 2 of 6466 chromosomes (freq: 0.0003), European in 14 of 126,688 chromosomes (freq: 0.0001), and South Asian in 24 of 30,782 chromosomes (freq: 0.0008); it was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Arg266 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.