17-35119613-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PVS1PS1_ModeratePP5BS2_Supporting

The NM_002878.4(RAD51D):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000435 in 1,611,004 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:2

Conservation

PhyloP100: 5.06

Publications

12 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 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 20 pathogenic variants. Next in-frame start position is after 16 codons. Genomic position: 35119568. Lost 0.047 part of the original CDS.

PS1

Another start lost variant in NM_002878.4 (RAD51D) was described as [Likely_pathogenic] in ClinVar

PP5

Variant 17-35119613-T-C is Pathogenic according to our data. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884. Variant chr17-35119613-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127884.

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 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.1A>G	p.Met1?	start_lost	Exon 1 of 10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.3+1678A>G		intron_variant	Intron 1 of 6	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246458

AF XY:

0.00000748

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458698

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111916

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

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

AF:

0.0000131

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:2Uncertain:1

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 127884). Disruption of the initiator codon has been observed in individual(s) with ovarian cancer and colon polyps and colon or ovarian cancer and a personal or family history of breast and/or ovarian cancer (PMID: 24130102, 26681312, 27978560, 30322717). This variant is present in population databases (rs561425038, gnomAD 0.006%). This sequence change affects the initiator methionine of the RAD51D mRNA. The next in-frame methionine is located at codon 16. -

Apr 06, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Oct 21, 2020

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant results in the loss of translation initiator codon of the RAD51D gene. Although functional studies have not been reported, this variant is expected to result in an absent or non-functional protein product. It has been shown that the highly conserved RAD51D N-terminus (a.a. 1-83) encodes the single-stranded DNA binding domain and that the 13-residue N-terminal tail (a.a. 1-13) contributes to proper protein folding via hydrophobic interactions between side chains of the N-terminal tail and alpha helices of the single-stranded DNA binding domain (PMID: 21111057). These findings suggest that the production of a full-length protein from p.Met1 is important for RAD51 function. While an in-frame methionine occurs at codon 16, it is not known if it can serve as an alternative translation initiation site to produce a functional RAD51D protein. This variant has been reported in an individual affected with ovarian cancer (PMID: 26681312) and in an individual affected with colorectal cancer (PMID: 27978560). A different nucleotide substitution with the same protein effect (c.1A>T) has also been reported in an individual affected with breast and ovarian cancer (PMID: 24130102). This variant has been identified in 1/246458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 27, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the RAD51D gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in unrelated women with ovarian cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Cardoso FC et al. Hum. Genomics, 2018 08;12:39; Carter NJ et al. Gynecol Oncol. 2018 12;151(3):481-488) as well as in a woman with early onset mismatch repair proficient colorectal cancer (Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1Uncertain:1

Jul 09, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Bewertung aller Varianten die das Startcodon betreffen im September!; According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (strong pathogenic): Frage zu PVS1-Bewertungsstärke: laut canvig RAD51C/D (=> Use ATM PVS1 Decision Tree): PVS1, (pathogene Variante upstream vom nächsten Startcodon) wie bewerten wir es? laut Toyun: PVS1-mod (pathogene Variante upstream vom nächsten Startcodon) Funktionelle Analyse: DNA BIndeDomäne , PM2 (supporting pathogenic): 1x in gnomAD V2 (non cancer oder all); 2x in gnomAD V3 (non cancer oder all) -

Jan 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

May 05, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26681312, 24130102, 27978560, 30103829) -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;D;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.44

PhyloP100

5.1

PROVEAN

Uncertain

-2.8

D;D;D;.

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.94

P;P;P;.

Vest4

0.95

MutPred

1.0

Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);

MVP

0.83

ClinPred

0.99

GERP RS

4.5

PromoterAI

-0.095

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.69

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

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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