17-35119588-C-G

Variant names:

• chr17-35119588-C-G
• rs140825795
• NM_002878.4:c.26G>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002878.4(RAD51D):​c.26G>C​(p.Cys9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,612,440 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).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:8
• Conservation: PhyloP100: 3.45

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23021111).
• BP6: Variant 17-35119588-C-G is Benign according to our data. Variant chr17-35119588-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127886.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=11}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000675 (986/1460118) while in subpopulation NFE AF= 0.000831 (924/1111920). AF 95% confidence interval is 0.000787. There are 1 homozygotes in gnomad4_exome. There are 499 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.26G>C	p.Cys9Ser	missense_variant	Exon 1 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.26G>C	p.Cys9Ser	missense_variant	Exon 1 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.3+1703G>C		intron_variant	Intron 1 of 6	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000372 AC: 92 AN: 247570 Hom.: 1 AF XY: 0.000410 AC XY: 55 AN XY: 134222

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000675 AC: 986 AN: 1460118 Hom.: 1 Cov.: 31 AF XY: 0.000687 AC XY: 499 AN XY: 726452

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000831

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74484

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000546 Hom.: 1

Bravo AF: 0.000423

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 09, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2019

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in individuals with breast and/or ovarian cancer (Wickramanayake 2012, Gutierrez-Enríquez 2014, Song 2015). This variant has an allele frequency of 0.0004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51D c.26G>C; p.Cys9Ser variant (rs140825795; ClinVar Variation ID: 127886), has been previously reported in several ovarian cancer cohort (selected references: Wickramanayake 2012 and Song 2015), but in many cases has was also identified in control populations (Weitzel 2019). This variant is found in the general population with an overall allele frequency of 0.04% (113/278,930 alleles) in the Genome Aggregation Database. The cysteine at codon 9 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.218). Based on the available information, the clinical significance of this variant is uncertain References: Song 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 Weitzel et al. Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer. 2019 Aug 15;125(16):2829-2836. PMID: 31206626 Wickramanayake et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012 Dec;127(3):552-5. PMID: 22986143 -

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. -

not provided Uncertain:3 Benign:2

Nov 18, 2024

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, ovarian, and/or colorectal cancer, as well as in controls (PMID: 21822267, 22986143, 24139550, 24130102, 26261251, 25186627, 28135145, 29522266, 31206626, 33471991, 36315097, 35264596, 34326862, 33606809, 32885271); 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: 22986143, 28135145, 21822267, 24130102, 26261251, 24139550, 25340522, 27498913, 25186627, 29522266, 31007844, 34117267, 33471991, 36315097, 31206626, 34923718, 35264596, 21111057, 35980532, 33606809, 33203166, 29641532, 30306255, 34326862, 32885271, 36977404) -

May 29, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51D: BP4, BS2 -

Aug 18, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: BP4 -

Oct 12, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 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.26G>C (p.Cys9Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 258298 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 3 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 benign. c.26G>C, has been reported in the literature in individuals affected with Breast and Ovarian Cancer or other cancers and also in controls (example, Wickramanyake_2012, Gutirrez-Enrquez_2013, Loveday_2011, Golmard_2013, Song_2015, Yurgelun_2017, Tung_2015, Madeddu_2019, Weitzel_2019). In addition, this variant has been reported in 10/9884 individuals who are at least 70 years old and cancer-free in the FLOSSIES database. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA1 c.5266dup, p.Gln1756fs) and reported in the literature (BRCA2 c.5851_5854del, p.Ser1951Trpfs*11, Tung_2015), providing supporting evidence for a benign role. 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: 25340522, 24139550, 24130102, 21822267, 31007844, 26261251, 25186627, 31206626, 22986143, 28135145). ClinVar contains an entry for this variant (Variation ID: 127886). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Mar 26, 2021

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. -

Jan 07, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with serine at codon 9 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 21822267, 22986143, 24130102, 24139550, 26261251), cervical cancer (PMID: 31007844) and healthy controls and unaffected individuals (PMID: 21822267, 26261251; FLOSSIES database at https://whi.color.com/variant/17-33446607-C-G). This variant has been identified in 113/278930 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 09, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Uncertain:1

Mar 08, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

The RAD51D p.Cys9Ser variant was identified in 9 of 12002 proband chromosomes (frequency: 0.0007) from Spanish, British and American individuals or families with BRCA1/2 negative breast/ovarian cancer or ovarian cancer and was identified in 3 of 7674 chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Loveday 2011, Wickramanayake 2012, Song 2015). A case-control study of 3,429 patients with invasive ovarian cancer (unselected for family history) and 2,772 controls sequenced for RAD51B/C/D mutations found that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes (Song 2015). The variant was identified in dbSNP (ID: rs140825795) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics Inc. and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and was not identified in Cosmic or LOVD 3.0. The variant was also identified in control databases in 109 (1 homozygous) of 273460 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 23938 chromosomes (freq: 0.0002), “Other” in 2 of 6436 chromosomes (freq: 0.0003), Latino in 13 (1 homozygous) of 34392 chromosomes (freq: 0.0004), European Non-Finnish in 88 of 124366 chromosomes (freq: 0.0007), European Finnish in 2 of 24602 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Cys9Ser 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, HumanSpliceFinder) 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. -

RAD51D-related disorder Benign:1

Mar 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M;M;M;M
PROVEAN	Pathogenic	-6.2	D;D;D;.
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Uncertain	0.0050	D;D;T;D
Polyphen		0.95	P;P;D;.
Vest4		0.76
MutPred		0.75		Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);
MVP		0.90
MPC		0.37
ClinPred		0.12	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		0.76

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: rs140825795; hg19: chr17-33446607;