17-58703264-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_058216.3(RAD51C):c.640C>T(p.Arg214Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000367 in 1,607,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:5

Conservation

PhyloP100: 3.87

Variant links:

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAD51C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07894361).

BP6

Variant 17-58703264-C-T is Benign according to our data. Variant chr17-58703264-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141324.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.640C>T	p.Arg214Cys	missense_variant	Exon 4 of 9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.640C>T	p.Arg214Cys	missense_variant	Exon 4 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251226

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1455710

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

724586

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000164

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

May 18, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 05, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:2

Nov 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Jun 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21980511 (2011), 25186627 (2015), (30093976 (2018), 33471991 (2021)), in an individua with endometrial cancer (PMID: 27443514 (2016)) as well as in unaffected controls (PMID: 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/ RAD51C)). In a yeast-two-hybrid assay, the variant resulted in reduced RAD51C protein level and binding with XRCC3 and RAD51B (PMID 21980511 (2011)). However, more recent studies using both cell-based homologous recombination (HR) assays and yeast analysis showed that the variant retained normal binding to RAD51D, RAD51B and XRCC3, and had proficient HR activity (PMIDs: 36099300 (2022) and 37253112 (2023)). The frequency of this variant in the general population, 0.00068 (17/24962 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 10, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies are inconclusive: demonstrates reduced binding with XRCC3 and RAD51B in one study, while another study showed RAD51D, RAD51B and XRCC3 binding similar to wild-type and proficient homologous recombination (HR) activity (Clague et al., 2011; Prakash et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23117857, 25186627, 25470109, 21980511, 27443514, 28829762, 30093976, 14704354, 36099300) -

not specified

Uncertain:1Benign:1

Jun 11, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAD51C c.640C>T (p.Arg214Cys) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251226 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.640C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Tung_2014, Ring_2016, Clague_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in small but significant reductions in interaction between RAD51C and both XRCC3 and RAD51B, but there were no marked changes in the steady-state level of RAD51C (Clague_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21980511, 23117857, 27443514, 25470109, 25186627). ClinVar contains an entry for this variant (Variation ID: 141324). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer

Uncertain:1

Sep 01, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RAD51C-related disorder

Uncertain:1

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51C c.640C>T variant is predicted to result in the amino acid substitution p.Arg214Cys. This variant has been reported in individuals with breast, ovarian, or endometrial cancer (Clague et al. 2011. PubMed ID: 21980511; Table 2, Kushnir et al. 2012. PubMed ID: 23117857; Table S2, Chan et al. 2018. PubMed ID: 30093976; Table S2, Ring et al. 2016. PubMed ID: 27443514; Table 2, Sopik et al. 2015. PubMed ID: 25470109; Table S1, Tung et al. 2014. PubMed ID: 25186627). It has also been observed as a somatic change in a colon adenocarcinoma (Table 1, Prakash et al. 2022. PubMed ID: 36099300). Functional studies of the p.Arg214Cys variant showed decreased protein interaction and suggest the variant may be hypomorphic (Clague et al. 2011. PubMed ID: 21980511). However, experimental studies using yeast-based assays suggest this variant does not impair protein interaction or homologous recombination ability (Figure 2, Prakash et al. 2022. PubMed ID: 36099300). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the vast majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/141324/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group O

Uncertain:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 214 of the RAD51C protein (p.Arg214Cys). This variant is present in population databases (rs140804406, gnomAD 0.06%). This missense change has been observed in individual(s) with breast, ovarian or endometrial cancer (PMID: 21980511, 25186627, 27443514, 30093976, 35534704). ClinVar contains an entry for this variant (Variation ID: 141324). 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) indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 21980511). 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. -

Ovarian cancer

Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3

Benign:1

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

T;T;T;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.0077

MetaRNN

Benign

0.079

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.68

.;.;N;.

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.5

.;.;N;N

REVEL

Benign

0.098

Sift

Benign

0.28

.;.;T;T

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.0010

.;.;B;.

Vest4

0.40, 0.39

MVP

0.83

MPC

0.31

ClinPred

0.037

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.46

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