rs387906843

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_002878.4(RAD51D):c.556C>T(p.Arg186*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000031 in 1,612,962 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 3.60

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:

ENSG00000267618 (HGNC:):

ENSG00000267618 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 17-35106406-G-A is Pathogenic according to our data. Variant chr17-35106406-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35106406-G-A is described in Lovd as [Pathogenic]. Variant chr17-35106406-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.556C>T	p.Arg186*	stop_gained	Exon 6 of 10	ENST00000345365.11	NP_002869.3	O75771-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 link	c.556C>T	p.Arg186*	stop_gained	Exon 6 of 10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

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:

0.0000401

AC:

AN:

249290

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000602

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1460806

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726582

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000269

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000892

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:8Other:1

Aug 07, 2011

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 08, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51D p.Arg186X variant was identified in 7 of 15516 proband chromosomes (frequency: 0.00045) from individuals or families with breast and/or ovarian cancer or at high risk of ovarian cancer and was not identified in 7744 control chromosomes from healthy individuals (Loveday 2011, Song 20015, Thompson 2013, Keen-Kim 2017, Osher 2012). The variant was also identified in dbSNP (ID: rs387906843) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified 5x as pathogenic by Ambry Genetics, Invitae, Counsyl, Color Genomics and GeneDx; classified as risk factor by OMIM), Clinvitae (same references as ClinVar), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 8 of 275060 chromosomes at a frequency of 0.00003 in the following populations: Ashkenazi Jewish in 4 of 10036 chromosomes (freq. 0.0004); European non-Finnish in 4 of 125824 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in 2 Canadian individuals with ovarian cancer from the same family, both of whom demonstrated loss of wild-type allele in DNA extracted from tumour cells (Osher 2012). In a 3-generation pedigree segregating ovarian cancer and breast cancer this variant was found in 4 members of the same family (Loveday 2011). The proband had ovarian cancer at age 38; the variant was also confirmed in her sister who had breast cancer at age 39, and two aunts who had breast cancer at age 58 and age 53. Four other relatives on whom no molecular testing could be done died of ovarian cancer ranging in age from 49 to 65 years. Loss of function variants of the RAD51D gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Jun 09, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg186*) 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 (rs387906843, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with ovarian and breast cancer (PMID: 21822267, 22415235, 23372765, 25445424, 26261251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30285). For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2016

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51D c.556C>T (p.Arg186*) variant causes the premature termination of RAD51D protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 36544182 (2022), 35641994 (2022), 32068069 (2020), 26261251 (2015)), breast cancer (PMID: 32885271 (2021), 30980208 (2019), 30165555 (2018), 23372765 (2013)), prostate cancer (PMID: 32338768 (2020)) and osteosarcoma (PMID: 32191290 (2020)). The frequency of this variant in the general population, 0.00059 (6/10256 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Sep 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); This variant is associated with the following publications: (PMID: 27273131, 32242007, 30165555, 32986223, 28888541, 21822267, 25445424, 19383352, 22415235, 26328243, 26261251, 27153395, 23372765, 29560538, 28724667, 28821472, 26057125, 28152038, 30111881, 28591191, 30980208, 26689913, 32068069, 32885271, 32338768, 32107557, 35641994, 33804961, 32191290, 36346689, 36544182, 36169650, 32359370, 33471991, 32295079) -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Mar 02, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 6 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 multiple individuals affected with ovarian cancer (PMID: 21822267, 22415235, 23372765, 26261251, 32068069, 36544182), breast cancer (PMID: 21822267, 22415235, 27153395, 27273131), and in an individual affected with endometrial and serous tubal intraepithelial cancer (PMID: 28821472). This variant has also been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000017). This variant has been identified in 12/280688 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. -

Nov 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R186* pathogenic mutation (also known as c.556C>T), located in coding exon 6 of the RAD51D gene, results from a C to T substitution at nucleotide position 556. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been described in several breast and/or ovarian cancer patients (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Osher D et al. Br. J. Cancer. 2012 Apr;106:1460-3; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Byers H et al. Eur. J. Hum. Genet. 2016 Nov;24:1591-1597; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This mutation has also been reported in an individual diagnosed with grade 2 papillary serous cystadenocarcinoma, in a pre-menopausal breast cancer patient who underwent oophorectomy and was found to have serous tubal intraepithelial cancer, and in prostate cancer patients (Thompson E et al. PLoS One. 2013;8:e54772; Harvey LFB et al. J Minim Invasive Gynecol. 2017 Aug;[Epub ahead of print]; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). 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

Mar 27, 2023

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 30, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD51D c.556C>T (p.Arg186X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51D protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation located downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg232X). Mutation taster predicts a damaging outcome for this variant. This variant was found in 6/115838 control chromosomes at a frequency of 0.0000518, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). It was reported in several breast and ovarian cancer patients indicating causality. In addition multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Breast and/or ovarian cancer

Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inherited breast cancer and ovarian cancer

Pathogenic:1

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited ovarian cancer (without breast cancer)

Pathogenic:1

Sep 24, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Supporting -

Malignant tumor of breast

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Ovarian neoplasm

Pathogenic:1

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.89

Vest4

0.93

GERP RS

4.0

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