rs762951311

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBS2_Supporting

The NM_002878.4(RAD51D):c.286G>T(p.Gly96Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000356 in 1,406,378 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.55

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:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

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/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.286G>T	p.Gly96Cys	missense_variant	4/10	ENST00000345365.11	NP_002869.3	O75771-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.286G>T	p.Gly96Cys	missense_variant	4/10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 linkuse as main transcript	c.4-944G>T		intron_variant		2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251408

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000356

AC:

AN:

1406378

Hom.:

Cov.:

AF XY:

0.00000570

AC XY:

AN XY:

702368

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000471

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 96 of the RAD51D protein (p.Gly96Cys). This variant is present in population databases (rs762951311, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23372765, 26534844). ClinVar contains an entry for this variant (Variation ID: 231684). 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 expected to disrupt RAD51D protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51D function (PMID: 30836272). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2023	The p.G96C variant (also known as c.286G>T), located in coding exon 4 of the RAD51D gene, results from a G to T substitution at nucleotide position 286. The glycine at codon 96 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in 1/741 familial breast cancer patients, but was absent from 303 breast/ovarian cancer kindreds, 16 ovarian cancer only kindreds, and a series of 245 unselected ovarian cancer patients (Thompson ER et al. PLoS ONE 2013; 8:e54772). In another study, this variant was detected in 1/660 women with familial breast cancer who were negative for mutations in the BRCA1 and BRCA2 genes (Li J et al. J. Med. Genet., 2016 Jan;53:34-42). Functional studies demonstrated this alteration led to impaired its interaction with XRCC2 and RAD51C and partially impaired HR-proficiency (Baldock RA et al. DNA Repair (Amst), 2019 04;76:99-107). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 13, 2021	This missense variant replaces glycine with cysteine at codon 96 of the RAD51D protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit partial loss of homology-directed repair activity compared to the wild type protein (PMID: 30836272). This variant has been reported in an individual affected with breast cancer (PMID: 23372765, 26534844) and, to our knowledge, has not been reported in individuals affected with ovarian cancer in the literature. This variant has been identified in 2/251408 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2021

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Thompson 2013, Li 2016); Published functional studies demonstrate a damaging effect: impaired interaction with XRCC2 and RAD51C and reduced homologous recombination activity (Baldock 2019); This variant is associated with the following publications: (PMID: 30836272, 21111057, 14704354, 27535533, 26534844, 23372765) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

4.4

H;H;.;.

PROVEAN

Pathogenic

-8.0

D;.;.;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.98

MutPred

0.94

Loss of catalytic residue at G96 (P = 0.105);Loss of catalytic residue at G96 (P = 0.105);.;.;

MVP

0.95

MPC

0.47

ClinPred

1.0

GERP RS

4.7

Varity_R

0.97

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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