17-35107074-C-T

Position:

chr17-35107074-C-T

Variant summary

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

The NM_002878.4(RAD51D):c.394G>A(p.Val132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,614,046 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 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:4O:1

Conservation

PhyloP100: 1.98

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=0.109271616).

BP6

Variant 17-35107074-C-T is Benign according to our data. Variant chr17-35107074-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185178.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Uncertain_significance=9}. Variant chr17-35107074-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.394G>A	p.Val132Ile	missense_variant	5/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.233-593G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.394G>A	p.Val132Ile	missense_variant	5/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251460

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000618

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:4Benign:1Other:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 132 of the RAD51D protein (p.Val132Ile). This variant is present in population databases (rs201141245, gnomAD 0.02%). This missense change has been observed in individual(s) with ‚Äãbreast and/or ovarian cancer and gastric cancer (PMID: 23372765, 26261251, 27616075, 32426482). ClinVar contains an entry for this variant (Variation ID: 185178). 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. -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	May 09, 2018	The RAD51D variant designated as NM_002878.3:c.394G>A (p.Val132Ile) is classified as likely benign. This variant is listed in ClinVar (Variation ID: 141739) and has been classified as likely benign by another laboratory. Computer software programs (SIFT, Polyphen-2, Align-GVGD) all predict that this variant is likely to be tolerated. In one observed family, this variant was not detected in an affected relativerâ€™s ovarian tumor, which indicates that it is unlikely to be the cause of her ovarian cancer. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about a 3% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter RAD51D function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 02-12-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 06, 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 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast or ovarian cancer and also in unaffected controls (PMID: 23372765, 26261251, 27616075, 30374176, 33471991, 35534704); This variant is associated with the following publications: (PMID: 23372765, 26261251, 27616075, 30374176, 29300386, 31159747, 32426482, 33471991, Giacomazzi2022[preprint], 14704354, 19327148, 21111057, 36243179, 35534704) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2017	Variant summary: The c.394G>A (p.Val132Ile) in RAD51D gene is a missense change that involves a non-conserved nucleotide. Although the variant is located within the ATP binding site of conserved domain Rad51_DMC1_radA, 4/5 in silico tools predict benign outcome. The variant is present in the large control population dataset of ExAC and gnomAD at a similar frequencies of 0.00007 (9/121398 and 17/277162 chrs tested, respectively), predominantly in individuals of African descent (0.0002884; 3/10404 and 6/24020 chrs tested) which exceeds the maximal expected frequency of a pathogenic allele (0.00012) in this gene. The variant has been reported in at least 1 sporadic brC case (Kraus, 2017) and 2 BrC families without strong evidence for causality (Thompson, 2013; Song, 2015). Lastly, several reputable databases/clinical laboratories cite the variant with classification of VUS but favoring the benign nature of this change. Taking all line of evidence into consideration, the variant was conservatively classified as VUS-Possibly Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 24, 2023	In the published literature, this variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 23372765 (2013), 26261251 (2015), 27616075 (2016)). This variant has also been reported in individuals with breast cancer and unaffected individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00024 (6/24958 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. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RAD51D p.Val132Ile variant was identified in 4 of 10,140 proband chromosomes (frequency: 0.0004) from individuals with breast and ovarian cancer and was not identified in 6476 control chromosomes from healthy individuals (Kraus 2017, Thompson 2013, Song 2015). The variant was identified in dbSNP (rs201141245) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, in ClinVar (interpreted as "uncertain significance" by Invitae and 4 others, "likely benign" by Ambry Genetics and 3 others). The variant was identified in control databases in 17 of 277,162 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24,020 chromosomes (freq: 0.0003), Latino in 4 of 34,418 chromosomes (freq: 0.0001), European in 6 of 126,668 chromosomes (freq: 0.00005), Finnish in 1 of 25,788 chromosomes (freq: 0.00004); it was not observed in the â€šÃ„ÃºOtherâ€šÃ„Ã¹, Ashkenazi Jewish, East Asian and South Asian populations. The variant was observed in our laboratory in an individual with a likely pathogenic BRCA1 variant (p.Val1833Met). The p.Val132 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

May 13, 2024

According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): REVEL Score: 0.229, BS1 (strong benign): TAF: 0.00005963 (gnomad 2.1, non-cancer) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.15

.;T;T;.;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.74

T;.;T;T;T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.11

T;T;T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.6

.;M;M;.;.;.

MutationTaster

Benign

1.0

D;D;N;N;N;N

PROVEAN

Benign

-0.83

.;N;.;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.034

.;D;.;.;.;.

Sift4G

Uncertain

0.045

D;D;D;D;T;.

Polyphen

0.42

.;B;B;.;.;.

Vest4

0.22, 0.22, 0.21

MVP

0.62

MPC

0.23

ClinPred

0.076

GERP RS

2.7

Varity_R

0.081

gMVP

0.38

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