17-35103294-T-C

Position:

• chr17-35103294-T-C

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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]

ENSG00000267618 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 138873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35103294-T-C is described in Lovd as [Benign]. Variant chr17-35103294-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1660 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.698A>G	p.Glu233Gly	missense_variant	8/10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.698A>G	p.Glu233Gly	missense_variant	8/10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.221A>G	p.Glu74Gly	missense_variant	4/7	2		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

GnomAD3 exomes AF: 0.00966 AC: 2374 AN: 245702 Hom.: 22 AF XY: 0.00973 AC XY: 1292 AN XY: 132732

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 SAS exome AF: 0.00315

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

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.00778

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00358

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0154

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

Gnomad4 AFR AF: 0.00321

Gnomad4 AMR AF: 0.00864

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00180

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0154 Hom.: 42

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 21, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2017	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

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2014	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. -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 26, 2014	- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Likely benign, no assertion criteria provided

clinical testing

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

Sep 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D;D;D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	.;.;.;L;L;.;.;.;.;.
PROVEAN	Uncertain	-3.4	.;.;.;D;.;.;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.065	.;.;.;T;.;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;T;T;T;T;D;D;.
Polyphen		0.97, 1.0	.;.;.;D;D;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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs28363284; hg19: chr17-33430313; COSMIC: COSV99047024; COSMIC: COSV99047024;