17-35119118-G-C

Position:

chr17-35119118-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_002878.4(RAD51D):c.137C>G(p.Ser46Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,613,388 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:2

Conservation

PhyloP100: 5.75

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

BP6

Variant 17-35119118-G-C is Benign according to our data. Variant chr17-35119118-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127882.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=12}.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.137C>G	p.Ser46Cys	missense_variant	2/10	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.137C>G	p.Ser46Cys	missense_variant	2/10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 linkuse as main transcript	c.3+2173C>G		intron_variant		2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251312

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.000123

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1461198

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.000129

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000315

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	Published functional studies demonstrates a damaging effect: decrease in protein stability resulting in defective homology directed repair activity (Alenezi et al., 2022); 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: 22986143, 27616075, 21822267, 35264596, 25938944, 35565380, 32522261, 34923718, 33630411, 33471991, 36315097, 21111057) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2023	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 35565380 (2022), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D), 27616075 (2016), 21822267 (2011), 22986143 (2012)), Lynch syndrome (PMID: 33630411 (2021)), and colorectal cancer (PMID: 25938944 (2015)). Additionally, the variant has been reported in healthy individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D), 22986143 (2012)). One experimental study reports the variant impacts proper RAD51D function, however further studies are needed to determine the global impact of this variant (PMID: 35565380 (2022)). The frequency of this variant in the general population, 0.00013 (17/129118 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 conflicting predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
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 14, 2024	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 46 of the RAD51D protein (p.Ser46Cys). This variant is present in population databases (rs587780102, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, multiple adenomatous polyps, and/or ovarian cancer (PMID: 22986143, 25938944, 27616075, 32522261, 33630411, 35565380). ClinVar contains an entry for this variant (Variation ID: 127882). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RAD51D function (PMID: 35565380). 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:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2023	Variant summary: RAD51D c.137C>G (p.Ser46Cys) results in a non-conservative amino acid change located in the RAD51D, N-terminal domain (IPR048943) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251312 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.00013), allowing no conclusion about variant significance. The variant was found in the FLOSSIES database in two European women older than age 70 years who have never had cancer. c.137C>G has been reported in the literature in individuals affected with Breast, Ovarian and Colorectal Cancer (Alenezi_2022, Kraus_2017, Wickramanayake_2012, Loveday_2011, Weren_2015, Velazquez_2020, Guindalini_2022, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported in a Lynch Syndrome case (MSH2 c.2459-1G>C, Ferrer-Avargues_2021). At least one publication reports experimental evidence evaluating an impact on protein function, suggesting impaired homologous recombination functionality (Alenezi_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35565380, 33630411, 35264596, 27616075, 21822267, 32522261, 25938944, 22986143, 35534704). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=10) and likely benign (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	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2023	This missense variant replaces serine with cysteine at codon 46 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). A functional study has shown the mutant protein to exhibit significantly reduced homology-directed DNA repair function and protein stability (PMID: 35565380). This variant has been observed in at least three individuals affected with ovarian cancer (PMID: 21822267, 22986143, 35565380), in an individual affected with breast cancer (PMID: 27616075), and an individual affected with multiple adenomatous polyps (PMID: 25938944). This variant has not shown a significant association with breast cancer in a large case-control study (3/60463 cases, 1/53460 controls; OR=2.653; 95%CI 0.276 to 25.502; p-value=0.628; Leiden Open Variation Database DB-ID FNDC8_000019) (PMID: 33471991). This variant has been observed in two individuals age 70 years or older without cancer (FLOSSIES; https://whi.color.com/variant/17-33446137-G-C). This variant has been identified in 22/282706 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2020	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 05, 2021	- -

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

Nov 03, 2020

- -

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.Ser46Cys variant was identified in 1 of 1172 proband chromosomes (frequency: 0.0009) from individuals or families with unselected ovarian cancer or at high risk of breast cancer (and negative for breast and ovarian cancer genes); it was identified in an ovarian cancer case (Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs587780102) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics, Invitae, ARUP Laboratories and Color Genomics Inc), and Clinvitae (3x), but was not identified in Cosmic and LOVD 3.0. The variant was identified in control databases in 25 of 276898 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 1 of 6464 chromosomes (freq: 0.0002), Latino in 4 of 34418 chromosomes (freq: 0.0001) and European Non-Finnish in 20 of 126540 chromosomes (freq: 0.0002); but not in the African, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ser46 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;D;.;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

.;D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

M;M;M;M;.

MutationTaster

Benign

1.0

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

PROVEAN

Uncertain

-3.8

D;D;D;.;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0060

D;D;D;.;.

Sift4G

Uncertain

0.023

D;D;D;D;.

Polyphen

1.0

D;D;D;.;.

Vest4

0.68

MVP

0.95

MPC

0.44

ClinPred

0.82

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.54

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