rs770250516

chr17-35103277-G-Achr17-35103277-G-Cchr17-35103277-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 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. R239G) 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:9 B:3
• Conservation: PhyloP100: 2.94

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.

• BP6: Variant 17-35103277-G-A is Benign according to our data. Variant chr17-35103277-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187225.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8}.
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.715C>T	p.Arg239Trp	missense_variant	8/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.467C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.715C>T	p.Arg239Trp	missense_variant	8/10	1	NM_002878.4	P1

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

GnomAD3 exomes AF: 0.0000285 AC: 7 AN: 245232 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132412

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 SAS exome AF: 0.0000337

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

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000332

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

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:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian cancer, some of whom are reported to also carry the pathogenic variant RAD51D Arg232Ter (Wickramanayake et al., 2012; Gutierrez-Enrquez et al., 2014; Song et al., 2015; Sanchez-Bermudez et al., 2018); This variant is associated with the following publications: (PMID: 24130102, 22986143, 26261251, 29409816, 35366121, 19327148, 21111057, 14704354) -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2022	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 16, 2021	- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

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
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
MutationTaster	Benign	0.52	D;D;D;D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs770250516; hg19: chr17-33430296;