rs769732230

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002878.4(RAD51D):c.878C>T(p.Ala293Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.374

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 links:

RAD51L3-RFFL (HGNC:):

RAD51L3-RFFL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14502504).

BP6

Variant 17-35101226-G-A is Benign according to our data. Variant chr17-35101226-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187161.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

BS2

High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.878C>T	p.Ala293Val	missense_variant	9/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.630C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.878C>T	p.Ala293Val	missense_variant	9/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251396

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of breast cancer who also carried variants in the PALB2 and FANCC genes (PMID: 34326862); Observed in healthy controls but absent from ovarian cancer cases, and present in both cases and controls in a breast cancer study (PMID: 26261251, 33471991); This variant is associated with the following publications: (PMID: 32863928, 33471991, 21111057, 14704354, 19327148, 26261251, 34326862) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RAD51D p.Ala293Val variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in the following databases: dbSNP (ID: rs769732230) as "With Uncertain significance allele", ClinVar (3x uncertain significance, 1x likely benign), and Clinvitae. The variant was not identified in the Cosmic database. The variant was identified in control databases in 8 of 277146 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 1 of 6466 chromosomes (freq: 0.0002), European in 3 of 126652 chromosomes (freq: 0.00002), East Asian in 2 of 18868 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Ala293 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2023	In the published literature, this variant has been reported in an individual with gastric cancer (PMID: 32863928 (2020)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). This variant has also been reported in unaffected individuals (PMID: 26261251 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). The frequency of this variant in the general population, 0.000023 (3/129114 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 29, 2016	- -

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.878C>T p.Ala293Val variant in the RAD51D gene has not been reported previously reported in individuals with Hereditary Breast and Ovarian Cancer Syndrome. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Benign/ Uncertain Significance multiple submissions. The amino acid Alanine at position 293 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala293Val in RAD51D is predicted as conserved by PhyloP across 100 vertebrates. Further studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 293 of the RAD51D protein (p.Ala293Val). This variant is present in population databases (rs769732230, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 187161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 08, 2024

Variant summary: RAD51D c.878C>T (p.Ala293Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 363862 control chromosomes (gnomAD, Song_2015, Dorling_2021). This frequency is not significantly higher than estimated for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (2.7e-05 vs 0.00013), allowing no conclusion about variant significance. c.878C>T has been reported in the literature in individuals affected with breast cancer or gastric cancer, as well as unaffected controls (e.g. Hu_2020, Dorling_2021, Lim_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 26261251, 32863928, 33471991, 34326862, 36315097). ClinVar contains an entry for this variant (Variation ID: 187161). Based on the evidence outlined above, the variant was classified as uncertain significance. -

RAD51D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 21, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.8

DANN

Benign

0.79

DEOGEN2

Benign

0.18

.;.;.;T;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.76

T;T;T;.;T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.4

.;.;.;L;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

-1.6

.;.;.;N;.;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.32

.;.;.;T;.;.;.;.

Sift4G

Benign

0.36

T;T;T;T;T;T;T;T

Polyphen

0.88, 0.88

.;.;.;P;P;P;.;.

Vest4

0.23

MVP

0.061

MPC

0.41

ClinPred

0.044

GERP RS

-6.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over