17-35103502-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002878.4(RAD51D):c.619T>C(p.Ser207Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,096 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6

Conservation

PhyloP100: 6.33

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.619T>C	p.Ser207Pro	missense_variant	Exon 7 of 10	ENST00000345365.11	NP_002869.3	O75771-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 link	c.619T>C	p.Ser207Pro	missense_variant	Exon 7 of 10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.142T>C	p.Ser48Pro	missense_variant	Exon 3 of 7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251418

Hom.:

AF XY:

0.00000736

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:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:1Uncertain:2

Feb 13, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 207 of the RAD51D protein (p.Ser207Pro). This variant is present in population databases (rs372365287, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 229719). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51D protein function. This variant disrupts the p.Ser207 amino acid residue in RAD51D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21822267, 22986143, 26845104, 26976419, 28646019). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

May 15, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A likely pathogenic mutation was detected in the RAD51D gene (c.283T>C). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 95 of the RAD51D protein (p.Ser95Pro). This variant is present in population databases (rs372365287, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 229719). Computational prediction suggests that this variant may have deleterious impact on protein structure and function . This variant disrupts the p.Ser95 amino acid residue in RAD51D. A different variant affecting the same codon position (p.Ser95Leu) is considered to be disease-causing (ClinVar variation ID: 142102), suggesting that serine at this position is important for protein structure and function (PMID: 21822267, 22986143, 26845104, 26976419, 28646019). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Pathogenic mutations in the RAD51D gene are associated with Breast-ovarian cancer, familial, susceptibility to, 4 (OMIM 614291 ). -

Hereditary cancer-predisposing syndrome

Uncertain:2

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S207P variant (also known as c.619T>C), located in coding exon 7 of the RAD51D gene, results from a T to C substitution at nucleotide position 619. The serine at codon 207 is replaced by proline, an amino acid with similar properties. This variant was identified in 1/177 individuals with pancreatic ductal adenocarcinoma undergoing multi-gene panel testing (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Apr 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with proline at codon 207 in the ATPase domain of the RAD51D protein. The RAD51D ATPase motif is required for resistance to DNA cross-linking agents and for interaction with RAD51C in homologous recombination (PMID: 16236763). This variant is located in the conserved Walker B motif that contributes a glutamic acid residue hydrolyzing ATP in the ATPase domain (PMID: 27941862, 37344587). This variant substitutes the conserved serine (residue 207) adjacent to the catalytic glutamic acid (residue 206) to proline in the RAD51D ATPase domain. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic ductal adenocarcinoma (PMID: 32255556). This variant has been identified in 3/282824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon (p.Ser207Leu) is considered to be disease-causing (ClinVar Variation ID: 142102), suggesting that serine at this position is important for protein structure and function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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

Mar 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with pancreatic ductal adenocarcinoma who also harbored missense variants in other potentially relevant genes (PMID: 32255556); This variant is associated with the following publications: (PMID: 21111057, 14704354, 16717288, 32255556) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jul 19, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Benign

0.37

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

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;.;D;T;D;T;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

4.3

.;.;.;H;H;.;.;.;.;.

PROVEAN

Pathogenic

-4.7

.;.;.;D;.;.;.;.;.;.

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;.;.;D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;T;D;D;D;.

Polyphen

1.0

.;.;.;D;D;D;.;.;.;.

Vest4

0.89

MutPred

0.82

.;.;.;Loss of catalytic residue at S207 (P = 0.0836);Loss of catalytic residue at S207 (P = 0.0836);.;.;.;.;.;

MVP

0.97

MPC

0.45

ClinPred

1.0

GERP RS

5.0

Varity_R

0.96

gMVP

0.85

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

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