17-35103294-T-C

Variant names:

• chr17-35103294-T-C
• rs28363284
• NM_002878.4:c.698A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002878.4(RAD51D):​c.698A>G​(p.Glu233Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,611,638 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E233D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.017 (285 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 3.00
• Publications: 34 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012577295).
• BP6: Variant 17-35103294-T-C is Benign according to our data. Variant chr17-35103294-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1660/152080) while in subpopulation NFE AF = 0.0192 (1303/67990). AF 95% confidence interval is 0.0183. There are 12 homozygotes in GnomAd4. There are 749 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1660 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002878.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	NM_002878.4	MANE Select	c.698A>G	p.Glu233Gly	missense	Exon 8 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.758A>G	p.Glu253Gly	missense	Exon 8 of 10	NP_001136043.1
	RAD51D	NM_133629.3		c.362A>G	p.Glu121Gly	missense	Exon 5 of 7	NP_598332.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.698A>G	p.Glu233Gly	missense	Exon 8 of 10	ENSP00000338790.6
	RAD51D	ENST00000586186.3	TSL:1	c.563A>G	p.Glu188Gly	missense	Exon 7 of 9	ENSP00000468273.3
	ENSG00000267618	ENST00000593039.5	TSL:2	c.221A>G	p.Glu74Gly	missense	Exon 4 of 7	ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1661 AN: 151962 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00322

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00966 AC: 2374 AN: 245702 AF XY: 0.00973

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00728

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0174 AC: 25453 AN: 1459558 Hom.: 285 Cov.: 32 AF XY: 0.0169 AC XY: 12235 AN XY: 725816

African (AFR) AF: 0.00302 AC: 101 AN: 33462

American (AMR) AF: 0.00778 AC: 345 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 45 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00358 AC: 307 AN: 85648

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53240

Middle Eastern (MID) AF: 0.00699 AC: 40 AN: 5724

European-Non Finnish (NFE) AF: 0.0212 AC: 23600 AN: 1111122

Other (OTH) AF: 0.0154 AC: 928 AN: 60296

GnomAD4 genome AF: 0.0109 AC: 1660 AN: 152080 Hom.: 12 Cov.: 32 AF XY: 0.0101 AC XY: 749 AN XY: 74352

African (AFR) AF: 0.00321 AC: 133 AN: 41460

American (AMR) AF: 0.00864 AC: 132 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.00180 AC: 19 AN: 10576

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1303 AN: 67990

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0150 Hom.: 75

Bravo AF: 0.0110

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.00874 AC: 1061

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Sep 09, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 04, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 13, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast-ovarian cancer, familial, susceptibility to, 4 Benign:4

Jun 09, 2016

Counsyl

Significance: Likely benign

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.

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 10, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

not provided Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 09, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD51D c.698A>G (p.Glu233Gly) variant locatedin the DNA recombination and repair protein RAD51-like, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2670/277696 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0164 (2034/124022, 20 homozygotes). This frequency is about 131 times the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple case-control studies also showed that this variant does not confer an increased risk to breast or ovarian cancer (Rodrguez-Lpez 2004, Dowty 2008, Jara 2010, Loveday 2011). Although, the variant was shown to confer a slight increased risk for breast cancer in the BRCA-negative only with BrC cases (p-value = 0.02), this finding was not reproducible in a second study in Chilean BRCA1/2 negative women with a positive family history of breast cancer (Rodrguez-Lpez 2004, Jara 2010). Several in-vitro studies on human cancer cell lines, RAD51D-deficient mouse embryonic fibroblasts, and Yeast two-hybrid analysis have reported increased resistance to DNA-damaging agents, increased cellular proliferation, and decreased interaction with RAD51C (Nadkarni_2009). However, these experimental models are generally considered as weak experimental evidence as it is not clear if the results and conclusions drawn from these studies are applicable to the mechanism and presentation of disease. Two computational studies reporting an effect of this variant on function provide conflicting results (Rodrguez-Lpez 2004 and Zhao_2014). In addition, multiple clinical diagnostic laboratories have classified the variant as likely benign/benign. Furthermore, multiple internal LCA samples report the variant to co-occur with another pathogenic variant: PALB2 - c.196C>T (p.Gln66X), MUTYH - c.1187G>A (p.Gly396Asp), BARD1 - c.1690C>T (p.Gln564X), and likely pathogenic, TP53, c.782+1G>T. Therefore, due to the high occurrence in controls, co-occurrences with another pathogenic variant, and no strong established associated risk, the variant of interest has been classified as benign".

Hereditary cancer-predisposing syndrome Benign:3

Jan 12, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 26, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51D p.Glu233Gly variant was identified in 252 of 14720 proband chromosomes (frequency: 0.017) from Spanish, Australian, British and Chilean individuals or families with BRCA1/BRCA2 negative breast and ovarian cancers (with or without family history), and was present in 134 of 8936 control chromosomes (frequency: 0.015) from healthy individuals (Song 2015 , Rodriguez-Lopez 2004, Osher 2012, Gutierrez-Enriquez 2013, Dowty 2007, Jara 2010). In multiple case control studies, there was no evidence to support an association between the variant and increased risk of breast cancer, nor any evidence of association between the RAD51D-E233G variant and BC who have a positive family history (Dowty 2007, Jara 2010), but rather a low penetrance susceptibility gene in high risk site specific familial breast cancer with segregation studies finding incomplete segregation with disease (Rodriguez-Lopez 2004). Rolland et al (2014) described a systematic map of human binary protein-protein interactions which showed that the variant affects interactions with a number of proteins, including the known cancer gene product IKZF1. Functional studies also suggest that the variant affects RAD51D functions and protein interactions, by increasing cellular resistance to DNA damaging agents (chemoresistant), contributing to telomere dysfunction by conferring cellular proliferation and decreasing the interaction with RAD51C (Nadkarni 2009). The variant was identified in dbSNP (ID: rs28363284) as “other”, Clinvitae database (classifications benign, likely benign and conflicting interpretations of pathogenicity), Leiden Open Variation Database (LOVD), the ClinVar database (classification benign by GeneDx, Ambry Genetics, Invitae, color Genomics Inc., and likely benign by Illumina and Counsyl). The variant was also identified in control databases in 2567 of 271538 (20 homozygous) chromosomes at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 2034 of 124022 chromosomes (freq: 0.02), and Other in 63 of 6354 chromosomes (freq: 0.01). The p.Glu233 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; however, 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

Hereditary breast ovarian cancer syndrome Benign:1

Sep 15, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.0
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.19
Sift	Benign	0.065	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.63
MVP		0.91
MPC		0.42
ClinPred		0.022	T
GERP RS		4.9
Varity_R		0.47
gMVP		0.65
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.090		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: rs28363284; hg19: chr17-33430313; COSMIC: COSV99047024; COSMIC: COSV99047024;