rs587780104

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

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 (★★). 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 0.540

Variant links:

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 links:

RAD51L3-RFFL (HGNC:):

RAD51L3-RFFL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.694C>T	p.Arg232Ter	stop_gained	8/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.446C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.694C>T	p.Arg232Ter	stop_gained	8/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

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:

AN:

245828

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

132778

show subpopulations

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:

AN:

1459582

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725848

show subpopulations

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:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

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.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:7

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	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	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	MGZ Medical Genetics Center	Jan 31, 2022	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RAD51D: PVS1, PM2, PS4:Moderate -
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, 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	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

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	- -
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; Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97; Sánchez-Bermúdez 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. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
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. -

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 -

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

- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over