rs387906843

Positions:

• chr17-35106406-G-A
• chr17-35106406-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002878.4(RAD51D):​c.556C>T​(p.Arg186Ter) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R186R) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 3.60

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 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 [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/exons	MANE	UniProt
RAD51D	NM_002878.4	c.556C>T	p.Arg186Ter	stop_gained	6/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.308C>T		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.556C>T	p.Arg186Ter	stop_gained	6/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 32

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: 10 AN: 249290 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134760

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: 46 AN: 1460806 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726582

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: 4 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

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.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 “With Pathogenic allele”, 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 laboratory’s criteria to be classified as pathogenic. -
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. -
risk factor, no assertion criteria provided	literature only	OMIM	Aug 07, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 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); 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

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2021	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 02, 2022	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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 “With Pathogenic allele”, 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 laboratory’s criteria to be classified as pathogenic. -

Ovarian neoplasm 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

-

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 30, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
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

Other links and lift over

dbSNP: rs387906843; hg19: chr17-33433425;