rs544654228

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002878.4(RAD51D):c.493C>T(p.Arg165Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,612,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:15B:1

Conservation

PhyloP100: 4.82

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002878.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAD51D	NM_002878.4	MANE Select	c.493C>T	p.Arg165Trp	missense	Exon 6 of 10	NP_002869.3
RAD51D	NM_001142571.2		c.553C>T	p.Arg185Trp	missense	Exon 6 of 10	NP_001136043.1
RAD51D	NM_133629.3		c.157C>T	p.Arg53Trp	missense	Exon 3 of 7	NP_598332.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.493C>T	p.Arg165Trp	missense	Exon 6 of 10	ENSP00000338790.6
RAD51D	ENST00000586186.3	TSL:1	c.358C>T	p.Arg120Trp	missense	Exon 5 of 9	ENSP00000468273.3
ENSG00000267618	ENST00000593039.5	TSL:2	c.16C>T	p.Arg6Trp	missense	Exon 2 of 7	ENSP00000466834.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

247668

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.0000641

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000536

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1460030

Hom.:

Cov.:

AF XY:

0.0000730

AC XY:

AN XY:

726106

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33448

American (AMR)

AF:

0.0000225

AC:

AN:

44472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000466

AC:

AN:

85822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

1111164

Other (OTH)

AF:

0.000116

AC:

AN:

60342

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

AF:

0.0000525

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:15Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:5

Aug 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 165 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In an international breast cancer case-control meta-analysis, this variant was detected in 10/60466 cases and 5/53461 unaffected controls (PMID: 33471991). This variant has also been reported in an individual affected with breast cancer, together with a pathogenic truncation variant in the ATM gene (PMID: 29371908). This variant has been reported in an unaffected control individual in a breast and ovarian cancer case-control study (PMID: 21822267). This variant has been identified in 13/279074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 05, 2018

True Health Diagnostics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R165W variant (also known as c.493C>T), located in coding exon 6 of the RAD51D gene, results from a C to T substitution at nucleotide position 493. The arginine at codon 165 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with breast and/or ovarian cancer who previously tested negative for a known familial BRCA1/2 mutation (Dominguez-Valentin M et al. Hered Cancer Clin Pract 2018 Jan;16:4). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Aug 13, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:3Benign:1

Feb 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 26, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 165 of the RAD51D protein (p.Arg165Trp). This variant is present in population databases (rs544654228, gnomAD 0.01%). This missense change has been observed in individual(s) with RAD51D-related conditions (PMID: 31159747, 34284872). ClinVar contains an entry for this variant (Variation ID: 127891). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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.

Dec 13, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

not provided

Uncertain:3

Aug 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD51D c.493C>T (p.Arg165Trp) variant has been reported in the published literature in individuals with breast cancer and a personal and/or family history of breast and/or ovarian cancer (PMID: 29371908 (2018), 31159747 (2019), 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D). It has also been observed in reportedly healthy individuals (PMIDs: 21822267 (2011), 26261251 (2015), 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D), 36243179 (2022)). The frequency of this variant in the general population, 0.00012 (3/24306 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

May 29, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26261251, 31159747, 32579932, 29371908, 21822267, 34284872, 33471991, 36243179, 21111057, 14704354, 39519399)

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RAD51D c.493C>T (p.Arg165Trp) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain; DNA recombination and repair protein RecA-like, ATP-binding domain; AAA+ ATPase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 259332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (4.6e-05 vs 0.00013), allowing no conclusion about variant significance. c.493C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Dominguez-Valentin_2018 and Krivokuca_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.9139C>T, p.Arg3047Ter), providing supporting evidence for a benign role. 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: 21822267, 26261251, 29371908, 34284872). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=9) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

Lynch syndrome 1

Pathogenic:1

Jun 05, 2019

Clinical Cancer Genetics and Family Consultants, Athens Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted RAD51D c.493C>T at the DNA level, p.Arg165Trp. The arginine residue is weakly conserved and there is a moderate physicochemical difference between Arginine and Tryptophan. This variant has not been reported in the literature in individuals with RAD51D related disease. It has never been reported so far in Greek population. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We observed this variant in a woman with ovarian cancer at the age of 44 years and her brother with undifferentiated gastric cancer at the age of 43 years. Two other sisters are healthy carriers at the age of 53 and 50 years. There was also ovarian and prostate cancer in second degree family members, from the paternal side. The phenotype in this family was consistent with Lynch Syndrome type II. This inherited syndrome in the above family has apparently a causative relation with RAD51D mutation c.493C>T, which is classified as likely pathogenic.

Breast and/or ovarian cancer

Uncertain:1

Mar 13, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial ovarian cancer

Uncertain:1

Jan 03, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.42

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.7

PhyloP100

4.8

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.29

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.96

Vest4

0.28

MutPred

0.53

Loss of disorder (P = 0.0172)

MVP

0.90

MPC

0.37

ClinPred

0.46

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.30

Mutation Taster

=56/44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over