rs750621215

chr17-35101206-G-Achr17-35101206-G-Cchr17-35101206-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1_StrongPP5_Very_StrongBS2

The NM_002878.4(RAD51D):c.898C>T(p.Arg300Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,996 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. R300R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 3.33

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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

PP5

Variant 17-35101206-G-A is Pathogenic according to our data. Variant chr17-35101206-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35101206-G-A is described in Lovd as [Pathogenic]. Variant chr17-35101206-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.898C>T	p.Arg300Ter	stop_gained	9/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.650C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.898C>T	p.Arg300Ter	stop_gained	9/10	1	NM_002878.4	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251356

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Arg300) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the RAD51D protein. This variant is present in population databases (rs750621215, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with personal and/or family history of breast cancer and/or ovarian cancer (PMID: 25452441, 26261251, 28724667, 29255180, 32885271). This variant is also known as c.958C>T (p.Arg320). ClinVar contains an entry for this variant (Variation ID: 185048). This variant is expected to delete amino acid residues Arg300-Thr328 of the RAD51D protein, thereby removing the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057). Although functional studies have not been done for this particular variant, experimental studies using yeast two-hybrid analysis have shown that the region of the RAD51D protein necessary for RAD51C complexing localizes to the last ~100 amino acids (PMID: 10749867, 14704354, 19327148). The data indicates that this variant likely disrupts this important RAD51D-RAD51C interaction. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 22, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 31, 2021	The RAD51D c.898C>T (p.Arg300Ter) change is a nonsense variant that is predicted to cause premature protein truncation. The variant is not expected to result in nonsense mediated decay, but it is predicted to cause loss of normal protein function through removal of the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). This variant has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-33428225-G-A?dataset=gnomad_r2_1). This variant has been reported in individuals with breast cancer (PMID: 30111881, 30165555, 25452441, 28724667), ovarian cancer (PMID: 26261251), and a control individual with a family history of breast cancer (PMID: 26261251). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1, PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 18, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 29 amino acids, are lost; Observed in individuals with a personal or family history including breast and ovarian cancer (Couch et al., 2015; Song et al., 2015; Sun et al., 2017; Konstanta et al., 2018; Akbar et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25344691, 29255180, 25452441, 26261251, 28152038, 28724667, 30165555, 30111881, 31589614, 14704354, 21111057, 19327148, 33471991, 31300551, 32885271, 32107557, 34923718, 33804961, 36185283, 36544182, 30675318, 31341520, 33858678, 35171259, 35710434, 35014770, 35186721) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2023	This nonsense variant is predicted to cause the premature termination of RAD51D protein synthesis. The frequency of this variant in the general population, 0.00016 (3/18392 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35710434 (2022), 36185283 (2022), 32885271 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D), 31300551 (2020), 30111881 (2018), 29255180 (2017), 28724667 (2017), 26261251 (2015), 25452441 (2015)), prostate cancer (PMID: 36095024 (2022)), pancreatic cancer (PMID: 35171259 (2022)), and lung cancer (PMID: 35273153 (2022)). This variant has additionally been reported in healthy individuals (PMIDs: 33804961 (2021), 34887416 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D), 32906206 (2020), 26261251 (2015)). Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 25, 2023	This variant changes 1 nucleotide in exon 9 of the RAD51D gene, creating a premature translation stop signal in the penultimate coding exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported for this variant, it is expected to disrupt the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148) and adversely impact RAD51D protein function. This variant has been observed in at least three individuals with ovarian cancer (PMID: 26261251, 33858678, 35186721, 36544182). It has also been reported in over ten individuals with breast cancer (PMID: 25452441, 28724667, 29255180, 30111881, 31300551, 32885271, 33471991, 36185283) and in several control subjects unaffected with cancer (PMID: 26261251, 33471991). This variant has been identified in 7/251356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2023	The p.R300* variant (also known as c.898C>T), located in coding exon 9 of the RAD51D gene, results from a C to T substitution at nucleotide position 898. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theRAD51D gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 28 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Structural analysis has revealed that this region contains a highly conserved ATP cap which functions to hold the ATP in place, and is likely to impact nucleoprotein filament stability (Amunugama R et al. J. Biol. Chem. 2012 Mar;287:8724-36). This alteration has been identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Song et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Sun J et al. Clin. Cancer Res. 2017 Oct 15;23:6113-6119; Konstanta I et al. J. Hum. Genet. 2018 Nov;63:1149-1158; Gomez-Puerto D et al. Front Oncol, 2022 Sep;12:963728; Yao H et al. BMC Cancer, 2022 Dec;22:1337). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2023	Variant summary: RAD51D c.898C>T (p.Arg300X) located in exon 9 results in a premature termination codon, predicted to cause a truncation of the encoded protein by deleting the last 29 amino acids of the RAD51D protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251356 control chromosomes. c.898C>T has been widely reported in the literature in individuals affected with tubo-ovarian carcinoma (TOC) and breast cancer (example, Yang_2020; Fostira_2020). One of these ascertained studies provided age-specific risk for TOC for women with pathogenic variants in RAD51D and also confirmed that pathogenic variants in RAD51D confer a moderate risk for breast cancer (Yang_2020). These data indicate that the variant is likely to be associated with disease. 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: 31300551, 32107557). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 01, 2023	- -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 20, 2021

- -

Neoplasm of ovary

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

China-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RAD51D p.Arg300* variant was identified in 3 of 10506 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer or invasive epithelial ovarian cancer (Couch 2015, Song 2015). The variant was also identified in dbSNP (ID: rs750621215) as "With Likely pathogenic allele ", and in ClinVar (classified as likely pathogenic by Invitae, Ambry Genetics and GeneDx). The variant was not identified in the Cosmic database. The variant was identified in control databases in 7 of 246158 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111630 chromosomes (freq: 0.00003), East Asian in 3 of 17248 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish populations. The c.898C>T variant leads to a premature stop codon at position 300, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51D gene are an established mechanism of disease in RAD51D-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

D;D;D;D;D;D

Vest4

0.88

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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