rs587781813

Variant names:

• chr17-35101308-G-A
• rs587781813
• NM_002878.4:c.796C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35101308-G-A
• chr17-35101308-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002878.4(RAD51D):​c.796C>T​(p.Arg266Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:18 B:3 O:1
• Conservation: PhyloP100: 5.32
• Publications: 8 publications found

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]

RAD51D Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3298671).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.796C>T	p.Arg266Cys	missense_variant	Exon 9 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.796C>T	p.Arg266Cys	missense_variant	Exon 9 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.319C>T	p.Arg107Cys	missense_variant	Exon 5 of 7	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251416 AF XY: 0.000169

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461860 Hom.: 1 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000791 AC: 88 AN: 1112008

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74462

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:18 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1 Uncertain:7 Benign:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 06, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 03, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:2

Mar 12, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Sep 15, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 27, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 20, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Apr 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Jun 01, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RAD51D-related disorder Uncertain:1

Feb 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 11, 2023

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cancer or benign tumor Uncertain:1

May 26, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary site-specific ovarian cancer syndrome Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;.;.;T;T;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.7	.;.;.;H;H;.;.;.
PhyloP100		5.3
PROVEAN	Pathogenic	-5.2	.;.;.;D;.;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.99, 1.0	.;.;.;D;D;D;.;.
Vest4		0.72
MutPred		0.62		.;.;.;Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);.;.;.;
MVP		0.87
MPC		0.49
ClinPred		0.41	T
GERP RS		4.9
Varity_R		0.49
gMVP		0.59
Mutation Taster		=78/22	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587781813; hg19: chr17-33428327; COSMIC: COSV60005260; COSMIC: COSV60005260;