rs770250516

Variant names:

• chr17-35103277-G-A
• rs770250516
• NM_002878.4:c.715C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35103277-G-A
• chr17-35103277-G-C
• chr17-35103277-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002878.4(RAD51D):​c.715C>T​(p.Arg239Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,014 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R239P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:3
• Conservation: PhyloP100: 2.94
• 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.715C>T	p.Arg239Trp	missense_variant	Exon 8 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.715C>T	p.Arg239Trp	missense_variant	Exon 8 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.238C>T	p.Arg80Trp	missense_variant	Exon 4 of 7	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000285 AC: 7 AN: 245232 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1458878 Hom.: 1 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 725390

African (AFR) AF: 0.000120 AC: 4 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.000891 AC: 5 AN: 5614

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110908

Other (OTH) AF: 0.0000332 AC: 2 AN: 60292

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:5

Mar 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51D c.715C>T; p.Arg239Trp variant (rs770250516; ClinVar Variation ID: 187225) is reported in the literature in individuals with breast, ovarian, or biliary tract cancers (de Oliveira 2022, Guindalini 2022, Okawa 2023, Song 2015); however, the variant was not determined to be causative. Additionally, this variant has been reported to co-occur with a pathogenic RAD51D variant (p.Arg232Ter) in individuals with ovarian cancer and in healthy carriers from multiple families (Gutierrez-Enriquez 2014, Sanchez-Bermudez 2018, Wickramanayake 2012). The p.Arg239Trp variant is observed in the general population with an overall allele frequency of 0.003% (9/276624 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.287). Due to limited information, the clinical significance of this variant is uncertain at this time. References: de Oliveira JM et al. The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. Eur J Hum Genet. 2022 Jul;30(7):818-823. PMID: 35534704. Guindalini RSC et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. 2022 Mar 9;12(1):4190. PMID: 35264596. Gutierrez-Enriquez S et al. About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants. Int J Cancer. 2014 May 1;134(9):2088-97. PMID: 24130102. Okawa Y et al. Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. J Hepatol. 2023 Feb;78(2):333-342. PMID: 36243179. Sanchez-Bermudez AI et al. Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet. 2018 Jun;61(6):355-361. PMID: 29409816. Song H et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol. 2015 Sep 10;33(26):2901-7. PMID: 26261251. Wickramanayake A et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012 Dec;127(3):552-5. PMID: 22986143. -

Aug 02, 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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 239 of the RAD51D protein (p.Arg239Trp). This variant is present in population databases (rs770250516, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 22986143, 24130102, 26261251, 29409816). ClinVar contains an entry for this variant (Variation ID: 187225). 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 not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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. -

not provided Uncertain:4

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast or ovarian cancer, some of whom are reported to also carry the pathogenic variant RAD51D p.Arg232Ter (PMID: 22986143, 24130102, 26261251, 29409816, 35264596, 35534704, 35980532); 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: 24130102, 22986143, 26261251, 29409816, 35366121, 36243179, 35534704, 19327148, 21111057, 14704354, 35264596, 35980532) -

Sep 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51D c.715C>T (p.Arg239Trp) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 26261251 (2015)), including a few who also carried the RAD51D c.694C>T (p.Arg232*) pathogenic variant (PMIDs: 22986143 (2012), 24130102 (2014), 29409816 (2018)). This variant has also been observed in individuals with breast cancer as well as in reportedly healthy individuals (PMIDs: 35264596 (2022), 36243179 (2022), 24130102 (2014), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00004 (5/126380 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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51D p.Arg239Trp variant was identified in 8 of 10584 proband chromosomes (frequency: 0.0008) from individuals or families with breast or ovarian cancer and was not identified in 5624 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Sanchez-Bermudez 2018, Song 2015, Wickramanayake 2012). The variant was also identified in several population studies with a co-occurring pathogenic RAD51D variant (c.694C>T, p.Arg232*) in multiple members of same families (Sanchez-Bermudez 2018, Gutierrez-Enriquez 2013, Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs770250516) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and four other submitters). The variant was identified in control databases in 9 of 271100 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6340 chromosomes (freq: 0.0002), European in 5 of 123902 chromosomes (freq: 0.00004), East Asian in 2 of 18598 chromosomes (freq: 0.0001), and South Asian in 1 of 29868 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Arg239 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 cancer-predisposing syndrome Uncertain:2 Benign:2

Sep 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 18, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 c.715C>T, located in exon 8 of the RAD51D gene, is predicted to result in the substitution of arginine by tryptophan at codon 239, p.(Arg239Trp). This variant is found in 9/263186 alleles at a frequency of 0.0034% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.287) suggests that it does not affect the protein function according Pejaver 2022 thresholds (PMID: 36413997) (BP4). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. It has been reported in the ClinVar database (3x likely benign, 9x uncertain significance) and in the LOVD database (6x uncertain significance). Based on the currently available information, c.715C>T is classified as an uncertain significance variant according to ACMG guidelines. -

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R239W variant (also known as c.715C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 715. The arginine at codon 239 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is reported to co-occur with the p.R232* (c.694C>T) pathogenic RAD51D mutation in a proband with ovarian cancer at age 43 (Wickramanyake A et al. Gynecol. Oncol. 2012 Dec;127:552-5). In another family, both alterations were found in a proband with ovarian cancer at age 44 and in four of her healthy siblings (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97). Both of these alteration are also reported in a third family with two sisters with ovarian cancer at ages 47 and 46 and their three unaffected children (Sanchez-Bermudez AI et al. Eur J Med Genet. 2018 Jun;61(6):355-361). This variant was reported 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 amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial ovarian cancer Uncertain:1

Apr 30, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	.;.;.;T;T;.;.;.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.5	.;.;.;M;M;.;.;.;.;.
PhyloP100		2.9
PROVEAN	Uncertain	-3.9	.;.;.;D;.;.;.;.;.;.
REVEL	Benign	0.29
Sift	Uncertain	0.0070	.;.;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;.
Polyphen		1.0, 1.0	.;.;.;D;D;D;.;.;.;.
Vest4		0.35
MutPred		0.47		.;.;.;Gain of catalytic residue at L237 (P = 0.0032);Gain of catalytic residue at L237 (P = 0.0032);.;.;.;.;.;
MVP		0.98
MPC		0.38
ClinPred		0.61	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.65
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs770250516; hg19: chr17-33430296;