rs587781813

Positions:

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

Variant summary

Our verdict is Likely benign. Variant got -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:16 B:3 O:1
• Conservation: PhyloP100: 5.32

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]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
RAD51D	NM_002878.4	c.796C>T	p.Arg266Cys	missense_variant	9/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.548C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.796C>T	p.Arg266Cys	missense_variant	9/10	1	NM_002878.4	P1

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

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251416 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135888

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 SAS exome AF: 0.000849

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.000182

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

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

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:16 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1 Uncertain:6 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 07, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 03, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 04, 2023	The frequency of this variant in the general population, 0.00085 (26/30616 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 31159747 (2019), 30111881 (2018), 29522266 (2018), 29470806 (2018), 23372765 (2013)). Additionally, in a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ RAD51D)). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2023	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 (Thompson et al., 2013; Hauke et al., 2018; Konstanta et al., 2018; Singh et al., 2018; Krivokuca et al., 2019; Tsaousis et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 30651582, 23372765, 25775023, 29522266, 30111881, 31159747, 29470806, 19327148, 14704354, 21111057, 36690744, 33471991, 26689913, 34284872) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 06, 2023	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 (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 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2024	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. -

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

Jun 01, 2023

- -

RAD51D-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Uncertain significance, criteria provided, single submitter

curation

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

Oct 11, 2023

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. -

Hereditary site-specific ovarian cancer syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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
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
MutationTaster	Benign	1.0	D;D;D;D;D;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

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

Publications

LitVar

Other links and lift over

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