rs587780105

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_002878.4(RAD51D):c.748delC(p.His250ThrfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000253 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H250H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.17

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RAD51D links:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-35101355-TG-T is Pathogenic according to our data. Variant chr17-35101355-TG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.748delC	p.His250ThrfsTer2	frameshift_variant	Exon 9 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 link	c.748delC	p.His250ThrfsTer2	frameshift_variant	Exon 9 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5 link	c.271delC	p.His91ThrfsTer2	frameshift_variant	Exon 5 of 7	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251058

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461544

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 21, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift 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: 26681312, 21822267, 25452441, 25445424, 26261251, 28152038, 31948886, 32107557, 28888541, 33804961, 35980532, 35534704, 33471991, 34326862, 33008098) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAD51D: PVS1, PS4:Moderate, PM2:Supporting -

Apr 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD51D c.748del (p.His250Thrfs*2) variant alters the translational reading frame of the RAD51D mRNA and causes the premature termination of RAD51D protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMIDs: 26261251 (2015), 26681312 (2015), 33008098 (2020)), breast cancer (PMIDs: 25452441 (2015), 26681312 (2015), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D)), and prostate cancer (PMID: 31948886 (2020)). The frequency of this variant in the general population, 0.000004 (1/251058 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:3

Feb 24, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 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.His250Thrfs*2) 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 (rs587780105, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 25452441, 26261251). ClinVar contains an entry for this variant (Variation ID: 127894). For these reasons, this variant has been classified as Pathogenic. -

Jan 05, 2024

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jul 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 1 nucleotide in exon 9 of the RAD51D gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in five individuals affected with ovarian cancer, including three individuals from the same family (PMID: 26261251, 33008098). This variant has been reported in an individual with triple-negative breast cancer (PMID: 25452441) and in an individual affected with prostate cancer and urogenital-seminoma (PMID: 37723522). This variant has been identified in 1/251058 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. -

Oct 17, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.748delC pathogenic mutation, located in coding exon 9 of the RAD51D gene, results from a deletion of one nucleotide at nucleotide position 748, causing a translational frameshift with a predicted alternate stop codon (p.H250Tfs*2). This variant has been detected in multiple breast and/or ovarian cancer cohorts (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Susswein LR et al. Genet Med, 2016 08;18:823-32; Barbosa A et al. Cancers (Basel), 2020 Sep;12), as well as in a prostate cancer patient (Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). In one study, this variant was reported in 2 of 60466 breast cancer cases and in 2 of 53461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Breast and/or ovarian cancer

Pathogenic:1

Nov 11, 2019

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial ovarian cancer

Pathogenic:1

Jan 22, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

May 08, 2017

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.748delC (p.His250Thrfs) 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. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple HBOC patients and is absent in 120950 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over