rs121917739

chr15-40718818-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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. 13/19 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RAD51
• 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 id is 13127.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51	NM_002875.5	c.449G>A	p.Arg150Gln	missense_variant	6/10	ENST00000267868.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51	ENST00000267868.8	c.449G>A	p.Arg150Gln	missense_variant	6/10	1	NM_002875.5	P1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152010 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251486 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135916

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 SAS exome AF: 0.0000327

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.: 1 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 726014

Gnomad4 AFR exome AF: 0.00524

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00149

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152128 Hom.: 1 Cov.: 31 AF XY: 0.00130 AC XY: 97 AN XY: 74364

Gnomad4 AFR AF: 0.00540

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.00155

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	Observed in individuals with breast cancer but also in controls (Kato 2000, Le Calvez-Kelm 2012, Ding 2018, Shin 2020); Published functional studies are inconclusive: retention of polymer formation, decreased single strand and double strand DNA binding activities, and conflicting ATP-hydrolyzing activity (Ishida 2007, Chen 2015); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports 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) -

not specified Benign:2

Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2018	- -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

RAD51-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.30
DEOGEN2	Benign	0.0055	T;.;T;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;.
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.0057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Benign	0.45	T
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;.
Polyphen		0.020, 0.0	.;B;B;.;.;.
Vest4		0.14, 0.16, 0.17
MVP		0.42
MPC		1.1
ClinPred		0.022	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26

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

LitVar

Other links and lift over

dbSNP: rs121917739; hg19: chr15-41011016; COSMIC: COSV51112740;