17-35103492-G-A

Position:

chr17-35103492-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting

The NM_002878.4(RAD51D):c.629C>T(p.Ala210Val) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,614,008 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: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 6.71

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

BS2

High AC in GnomAd4 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.629C>T	p.Ala210Val	missense_variant	7/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.381C>T		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.629C>T	p.Ala210Val	missense_variant	7/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152134

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251402

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

181

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.000153

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74322

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

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	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 02, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 210 of the RAD51D protein (p.Ala210Val). This variant is present in population databases (rs376855484, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian cancer, breast cancer, pancreatic cancer, colon cancer and an individual undergoing Lynch syndrome testing (PMID: 24130102, 25452441, 25980754, 26057125, 26261251, 27978560, 28726808). ClinVar contains an entry for this variant (Variation ID: 141969). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 13, 2016	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family history of ovarian, breast, or other cancers, and also in unaffected controls from a breast cancer study (PMID: 24130102, 25452441, 26057125, 26261251, 25980754, 27978560, 28726808, 32756499, 33471991, 32885271); This variant is associated with the following publications: (PMID: 32322110, 24130102, 26057125, 25452441, 26261251, 25980754, 27978560, 28726808, 32756499, 33471991, 32885271, 21111057, 14704354, 34326862) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2022	This missense variant replaces alanine with valine at codon 210 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 multiple individuals affected with ovarian cancer (PMID: 24130102, 26057125, 26261251), breast cancer (PMID: 25452441), Lynch syndrome associated cancers and/or polyps (PMID: 25980754, 27978560), and pancreatic cancer (PMID: 28726808). It has also been observed in unaffected individuals (PMID: 33471991; Color internal data). This variant has been identified in 8/282794 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	clinical testing	Ambry Genetics	Nov 17, 2022	The p.A210V variant (also known as c.629C>T), located in coding exon 7 of the RAD51D gene, results from a C to T substitution at nucleotide position 629. The alanine at codon 210 is replaced by valine, an amino acid with similar properties. This alteration has been reported in individuals affected with breast, ovarian, pancreatic, and colon cancer (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May; Couch FC et al. J. Clin. Oncol. 2015 Feb;33:304-11134:2088-97; Velázquez C et al. Cancers (Basel), 2020 Aug;12; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Dorling et al. N Engl J Med. 2021 02;384:428-439; Janatova M et al. PLoS ONE. 2015 Jun;10:e0127711; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Chaffee KG et al. Genet Med, 2018 01;20:119-127; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). 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	curation	Sema4, Sema4	Feb 17, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 13, 2020

Variant summary: RAD51D c.629C>T (p.Ala210Val) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 257026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.629C>T has been reported in the literature in individuals affected with Breast/Ovarian Cancer Syndrome, Lynch syndrome, or pancreatic cancer (Gutierrez-Enrquez_2014, Couch_2015, Yurgelun_2015, Janatova_2015, Song_2015, Pearlman_2016, Chaffee_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

RAD51D-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2024

The RAD51D c.629C>T variant is predicted to result in the amino acid substitution p.Ala210Val. This variant has been reported in patients with breast, ovarian, prostate, pancreas and colorectal cancer, although conclusive evidence of pathogenicity was not presented (Gutiérrez-Enríquez et al. 2014. PubMed ID: 24130102; Table S6, Couch et al. 2014. PubMed ID: 25452441; Janatova et al. 2015. PubMed ID: 26057125; Table S4, Bhai et al. 2021. PubMed ID: 34326862). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed as uncertain in ClinVar by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/141969/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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.Ala210Val variant was identified in 8 of 16,500 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome, or pancreatic, breast or ovarian cancer and was not identified in 5538 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Couch 2015, Yurgelun 2015, Janatova 2015, Song 2015, Pearlman 2017, Chaffee 2018). The variant was identified in dbSNP (rs376855484) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics and 2 other submitters). The variant was identified in control databases in 8 of 282,794 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 7 of 129,124 chromosomes (freq: 0.00005) and African in 1 of 24,958 chromosomes (freq: 0.00004), while it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Ala210 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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) 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Aug 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.97

DEOGEN2

Benign

0.33

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

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.87

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

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.3

.;.;.;M;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Uncertain

-3.4

.;.;.;D;N;.;.;.;.;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.73

MutPred

0.74

.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;.;.;

MVP

0.95

MPC

0.40

ClinPred

0.84

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.59

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