rs587780104

chr17-35103298-G-Achr17-35103298-G-Cchr17-35103298-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_002878.4(RAD51D):c.694C>T(p.Arg232Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,611,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R232R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RAD51D NM_002878.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 0.540

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-35103298-G-A is Pathogenic according to our data. Variant chr17-35103298-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35103298-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.694C>T	p.Arg232Ter	stop_gained	8/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.446C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.694C>T	p.Arg232Ter	stop_gained	8/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152144 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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245828 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459582 Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 5 AN XY: 725848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

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: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Arg232*) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is present in population databases (rs587780104, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22986143, 24130102, 26057125, 26681312, 27083178, 28423363). ClinVar contains an entry for this variant (Variation ID: 127893). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with RAD51D-related cancers (Gutierrez-Enriquez et al., 2014; Wickramanayake et al., 2012; Janatova et al., 2015; Gonzalez-Rivera et al., 2016; Lilyquist et al., 2017; Tedaldi et al., 2017; Sanchez-Bermudez et al., 2018; Suszynska et al., 2020; Hauke et al., 2021); This variant is associated with the following publications: (PMID: 28423363, 28985766, 25445424, 24130102, 22986143, 26057125, 26720728, 27083178, 26681312, 29409816, 29470806, 24240112, 31589614, 32295079, 26689913, 30306255, 32318955, 32107557, 32359370, 29522266, 32980694, 34923718, 28888541, 35264596, 35565380, 33804961, 34308104) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 07, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RAD51D: PVS1, PM2, PS4:Moderate -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2022	The p.R232* pathogenic mutation (also known as c.694C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 694. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been identified in several patients diagnosed with ovarian carcinoma with a family history of breast and/or ovarian cancer (Wickramanayake A et al. Gynecol. Oncol. 2012 Dec;127:552-5; Guti&eacute;rrez-Enr&iacute;quez S et al. Int. J. Cancer. 2014 May;134:2088-97; S&aacute;nchez-Berm&uacute;dez AI et al. Eur J Med Genet 2018 Jun;61:355-361). It was also observed in two Czech women with high-grade serous adenocarcinoma diagnosed under the age of 45 with no family history of malignancy; in one woman with a personal history of triple negative breast cancer; and in one woman with a personal history of DCIS at age 47 and ovarian cancer at age 54 (Janatova M et al. PLoS ONE. 2015 Jun;10:e0127711; Gonzalez-Rivera M et al. Breast Cancer Res. Treat. 2016 04;156:507-515; Tedaldi G et al. Oncotarget. 2017 Jul;8:47064-4707). One study has estimated ovarian cancer risk for this variant (OR 16.07, 95% of 5.12-50.46; p value <0.0001) (Suszynska M et al. J Ovarian Res, 2020 May;13:50). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2022	This variant changes 1 nucleotide in exon 8 of the RAD51D gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with ovarian cancer (PMID: 22986143, 24130102, 26057125, 28423363). In a large breast cancer case-control study, this variant was identified in 12/60454 cases and 5/53456 controls; OR=2.122 (95%CI 0.748 to 6.024); p-value=0.223 (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000003). This variant has been identified in 4/277224 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 16, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2019	Variant summary: RAD51D c.694C>T (p.Arg232X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.748delC, p.His250fsX2). The variant allele was found at a frequency of 1.8e-05 in 274154 control chromosomes. c.694C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Wickramanayake_2012, Gutierrez-Enriquez_2014, Janatova_2015, Gonzalez-Rivera_2016, Tedaldi_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Colorectal cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Jan 04, 2022

ACMG criteria used to clasify this variant: PVS1, PS4, PM2 -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Diffuse midline glioma, H3 K27-altered Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Oct 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.56	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.92
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs587780104; hg19: chr17-33430317; COSMIC: COSV105193541; COSMIC: COSV105193541;