15-40718818-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002875.5(RAD51):c.449G>A(p.Arg150Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000321 in 1,611,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R150W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

RAD51
NM_002875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:5

Conservation

PhyloP100: 4.19

Publications

35 publications found

Variant links:

Genes affected

RAD51 (HGNC:9817): (RAD51 recombinase) 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, and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with the ssDNA-binding protein RPA and RAD52, and it is thought to play roles in homologous pairing and strand transfer of DNA. This protein is also found to interact with BRCA1 and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

RAD51 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group R
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
mirror movements 2
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
familial congenital mirror movements
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

RAD51 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057479143).

BP6

Variant 15-40718818-G-A is Benign according to our data. Variant chr15-40718818-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13127.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00156 (237/152128) while in subpopulation AFR AF = 0.0054 (224/41504). AF 95% confidence interval is 0.00482. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51	NM_002875.5 link	c.449G>A	p.Arg150Gln	missense_variant	Exon 6 of 10	ENST00000267868.8	NP_002866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RAD51	ENST00000267868.8 link	c.449G>A	p.Arg150Gln	missense_variant	Exon 6 of 10	1	NM_002875.5	ENSP00000267868.3
RAD51	ENST00000532743.6 link	c.449G>A	p.Arg150Gln	missense_variant	Exon 6 of 10	2		ENSP00000433924.2
RAD51	ENST00000557850.5 link	c.226-68G>A		intron_variant	Intron 3 of 7	2		ENSP00000454176.1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00539

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000366

AC:

AN:

251486

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1458976

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

726014

show subpopulations

African (AFR)

AF:

0.00524

AC:

175

AN:

33406

American (AMR)

AF:

0.000268

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00149

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1109496

Other (OTH)

AF:

0.000382

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00156

AC:

237

AN:

152128

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00540

AC:

224

AN:

41504

American (AMR)

AF:

0.000524

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000610

Hom.:

Bravo

AF:

0.00155

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:1

Feb 19, 2025

3billion

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v4.1.0 dataset. The variant is observed as heterozygous in at least one individual/adult in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.67 (>=0.6, sensitivity 0.72 and precision 0.9)]. The variant has been reported at least twice as benign with clinical assertions and evidence for the classification (ClinVar ID: VCV000013127). However, the variant has been reported to be associated with bilateral breast cancer (PMID: 10807537). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Jan 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Uncertain:1Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 14, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with breast cancer but also in controls (PMID: 10807537, 23300655, 28864920, 32019277); Published functional studies are inconclusive: retention of polymer formation, decreased single strand and double strand DNA binding activities, and conflicting ATP-hydrolyzing activity (PMID: 17666788, 25539919); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17666788, 10807537, 25539919, 23300655, 28864920, 27153395, 16762046, 32019277, 30271574, 31589614, 35534704, 35273153, 37588055)

not specified

Benign:2

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.052, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error.

Mar 06, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAD51-related disorder

Benign:1

Apr 14, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.0055

T;.;T;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.084

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D;D;.;D;.

M_CAP

Benign

0.0087

MetaRNN

Benign

0.0057

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N;.;.;.

PhyloP100

4.2

PrimateAI

Benign

0.45

PROVEAN

Benign

1.1

N;N;N;N;N;.

REVEL

Benign

0.10

Sift

Benign

0.74

T;T;T;T;T;.

Sift4G

Benign

0.84

T;T;T;T;T;.

Vest4

0.0

ClinPred

0.022

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over