rs544654228

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002878.4(RAD51D):c.493C>T(p.Arg165Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,612,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:13

Conservation

PhyloP100: 4.82

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_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.493C>T	p.Arg165Trp	missense_variant	6/10	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.493C>T	p.Arg165Trp	missense_variant	6/10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 linkuse as main transcript	c.16C>T	p.Arg6Trp	missense_variant	2/7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000404

AC:

AN:

247668

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

133870

show subpopulations

Gnomad AFR exome

AF:

0.0000641

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000665

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000536

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1460030

Hom.:

Cov.:

AF XY:

0.0000730

AC XY:

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000774

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 03, 2024	The p.R165W variant (also known as c.493C>T), located in coding exon 6 of the RAD51D gene, results from a C to T substitution at nucleotide position 493. The arginine at codon 165 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with breast and/or ovarian cancer who previously tested negative for a known familial BRCA1/2 mutation (Dominguez-Valentin M et al. Hered Cancer Clin Pract 2018 Jan;16:4). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 27, 2022	This missense variant replaces arginine with tryptophan at codon 165 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer, together with a pathogenic truncation variant in the ATM gene (PMID: 29371908). This variant has been reported in an unaffected control individual in a breast and ovarian cancer case-control study (PMID: 21822267). This variant has been identified in 13/279074 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 13, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26261251, 31159747, 32579932, 29371908, 21822267, 21111057, 14704354, 34284872, 33471991, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 05, 2024	The RAD51D c.493C>T (p.Arg165Trp) variant has been reported in the published literature in individuals with breast cancer and a personal and/or family history of breast and/or ovarian cancer (PMID: 29371908 (2018), 31159747 (2019), 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D). It has also been observed in reportedly healthy individuals (PMIDs: 21822267 (2011), 26261251 (2015), 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D), 36243179 (2022)). The frequency of this variant in the general population, 0.00012 (3/24306 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2023	Variant summary: RAD51D c.493C>T (p.Arg165Trp) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain; DNA recombination and repair protein RecA-like, ATP-binding domain; AAA+ ATPase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 259332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (4.6e-05 vs 0.00013), allowing no conclusion about variant significance. c.493C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Dominguez-Valentin_2018 and Krivokuca_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.9139C>T, p.Arg3047Ter), providing supporting evidence for a benign role. 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: 21822267, 26261251, 29371908, 34284872). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=9) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 165 of the RAD51D protein (p.Arg165Trp). This variant is present in population databases (rs544654228, gnomAD 0.01%). This missense change has been observed in individual(s) with RAD51D-related conditions (PMID: 31159747, 34284872). ClinVar contains an entry for this variant (Variation ID: 127891). 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%. 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. -

Lynch syndrome 1

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Clinical Cancer Genetics and Family Consultants, Athens Medical Center

Jun 05, 2019

This variant is denoted RAD51D c.493C>T at the DNA level, p.Arg165Trp. The arginine residue is weakly conserved and there is a moderate physicochemical difference between Arginine and Tryptophan. This variant has not been reported in the literature in individuals with RAD51D related disease. It has never been reported so far in Greek population. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We observed this variant in a woman with ovarian cancer at the age of 44 years and her brother with undifferentiated gastric cancer at the age of 43 years. Two other sisters are healthy carriers at the age of 53 and 50 years. There was also ovarian and prostate cancer in second degree family members, from the paternal side. The phenotype in this family was consistent with Lynch Syndrome type II. This inherited syndrome in the above family has apparently a causative relation with RAD51D mutation c.493C>T, which is classified as likely pathogenic. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.42

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.43

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

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.7

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

PROVEAN

Uncertain

-3.2

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

REVEL

Benign

0.29

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.96, 1.0

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

Vest4

0.28

MutPred

0.53

.;.;Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);.;.;.;.;

MVP

0.90

MPC

0.37

ClinPred

0.46

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.30

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