chr17-58720767-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_058216.3(RAD51C):c.859A>G(p.Thr287Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0088 in 1,612,322 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0091 ( 77 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:32

Conservation

PhyloP100: 4.88

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012393534).

BP6

Variant 17-58720767-A-G is Benign according to our data. Variant chr17-58720767-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 132702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58720767-A-G is described in Lovd as [Benign]. Variant chr17-58720767-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0063 (960/152314) while in subpopulation NFE AF= 0.0103 (699/68024). AF 95% confidence interval is 0.00964. There are 3 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.859A>G	p.Thr287Ala	missense_variant	Exon 6 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.859A>G	p.Thr287Ala	missense_variant	Exon 6 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.00631

AC:

961

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00560

AC:

1407

AN:

251152

Hom.:

AF XY:

0.00548

AC XY:

744

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00590

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000651

Gnomad NFE exome

AF:

0.00961

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.00907

AC:

13236

AN:

1460008

Hom.:

Cov.:

AF XY:

0.00876

AC XY:

6361

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.00156

Gnomad4 AMR exome

AF:

0.00651

Gnomad4 ASJ exome

AF:

0.000728

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000790

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00793

GnomAD4 genome

AF:

0.00630

AC:

960

AN:

152314

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

421

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.00895

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.0103

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00761

Hom.:

Bravo

AF:

0.00695

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0102

AC:

ExAC

AF:

0.00542

AC:

658

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00889

EpiControl

AF:

0.00996

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:32

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:9

May 09, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD51C c.859A>G (p.Thr287Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 693/126274 control chromosomes (3 homozygotes) at a frequency of 0.0054881, which is approximately 88 times the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients (including BrC, OvC, PcC) and some studies reported comparable frequencies of variant in case and controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign, without evidence to independently evaluate. Complementation assays of T287A have shown that a normal number of RAD51C foci are formed. Cells survival is reduced by ~36% in chicken DT40 cells, which may not be replicated in mammalian cells or associated with the pathology of HBOC (Meindl_2010). Considering all evidence, this variant is classified as benign. -

Jun 17, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51C: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:7

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 05, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Jun 27, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Dec 10, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 05, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Fanconi anemia complementation group O

Benign:3

Jun 13, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3

Benign:3

Jun 13, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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]. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Feb 28, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RAD51C-related disorder

Benign:1

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51C p.Thr287Ala variant was identified in 57 of 8266 proband chromosomes (frequency: 0.007) from Australian, British, German, American, Jewish and Other individuals or families with non- BRCA1/BRCA2 (high risk or familial) breast and/or ovarian cancer and was identified in 35 of 6604 control chromosomes (frequency: 0.005) from healthy individuals (Thompson 2012, Neidhardt 2017, Meindl 2009, Lu 2012, Clague 2011, Kushnir 2012, Leeneer 2012, Lu 2012). Three groups assessed RAD51C protein function for this variant, genomic stability and homologous recombination through functional assays and found that the variant is hypomorphic (Meindl 2009, Somyajit 2012, Clague 2011). However, complementation studies of this variant with a mutant RAD51C human fibroblast cell line demonstrated correction of the phenotype. The variant was also identified in dbSNP (ID: rs28363317) as â€šÃ„ÃºOtherâ€šÃ„Ã¹, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics, Children's Hospital of Philadelphia, Color Genomics; and likely benign by Illumina, Counsyl, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics), and LOVD 3.0 (9X); but was not identified in Clinvitae, Cosmic, and MutDB databases. The variant was identified in control databases in 1542 (6 homozygous) of 276966 chromosomes at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The p.Thr287Ala residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 this variant meets our laboratory's criteria to be classified as benign. -

Breast and Ovarian Cancer Susceptibility

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Sep 27, 2021

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.2

.;M;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.1

.;D;.

REVEL

Benign

0.14

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.046

D;T;D

Polyphen

0.99

.;D;.

Vest4

0.61

MVP

0.77

MPC

0.74

ClinPred

0.044

GERP RS

5.1

Varity_R

0.77

gMVP

0.81

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