rs587780256

Positions:

chr17-58696794-T-C

Variant summary

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

The NM_058216.3(RAD51C):c.506T>C(p.Val169Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V169V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:11

Conservation

PhyloP100: 3.43

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=0.17087844).

BP6

Variant 17-58696794-T-C is Benign according to our data. Variant chr17-58696794-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128206.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=7, Benign=1}. Variant chr17-58696794-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.506T>C	p.Val169Ala	missense_variant	3/9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.506T>C	p.Val169Ala	missense_variant	3/9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251466

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

306

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000262

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2024	The RAD51C c.506T>C (p.Val169Ala) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 20400964 (2010), 21990120 (2012), 22370629 (2012), 22476429 (2012), 22538716 (2012), 32885271 (2021), 34326862 (2021)). The variant has also been identified in individuals affected with diverse cancers including endometrial cancer (PMIDs: 26689913 (2015), 27443514 (2016)), Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 (2015)), leukemias (PMIDs: 18203022 (2008), 37450374 (2023)), low grade glioma (PMID: 26689913 (2015)), and others (PMID: 32885271 (2021)). Despite its occurrence in several published patients, other studies have also identified the variant in several reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)) and was described as being unlikely to cause breast cancer (PMID: 35039523 (2022)). The frequency of this variant in the general population, 0.0005 (13/26132 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Functional studies in vitro have observed that the variant corrected MMC hypersensitivity in chicken DT40 cells (PMID: 20400964 (2010)), restored RAD51 foci formation in human fibroblasts (PMID: 20400964 (2010)), and had DNA repair (HDR) activity in hamster cells comparable to the wild-type (PMID: 37253112 (2023)). A published report in a family affected with breast cancer also suggests this variant may not be responsible for the disease (PMID: 36368728 (2022)), however the available information was limited. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RAD51C: BP4, BS3:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2021	This variant is associated with the following publications: (PMID: 26689913, 18203022, 28829762, 21537932, 20400964, 25470109, 22370629, 22476429, 25980754, 21990120, 25801821, 27443514, 23117857, 26261251, 22538716) -

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 01, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 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. -

Fanconi anemia complementation group O

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 169 of the RAD51C protein (p.Val169Ala). This variant is present in population databases (rs587780256, gnomAD 0.03%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 18203022, 20400964, 21990120, 22370629, 22476429, 22538716, 25980754, 26689913, 27443514, 34326862). This variant is also known as 4150T>C. ClinVar contains an entry for this variant (Variation ID: 128206). 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 does not substantially affect RAD51C function (PMID: 20400964). 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	Counsyl	Jul 11, 2016	- -

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 14, 2022

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RAD51C p.Val169Ala variant was identified in 11 of 30,036 proband chromosomes (frequency: 0.0004) from individuals or families with chronic lymphocytic leukemia, Lynch Syndrome, glioma, endometrial, and hereditary breast and ovarian cancer and was present in 2 of 16,372 control chromosomes (frequency: 0.0001) from healthy individuals (Sellick 2008, Meindl 2009, Lu 2012, De Leeneer 2012, Thompson 2012, Loveday 2012, Yurgelun 2015, Ring 2016, Lu 2015, Song 2015). The variant was identified in dbSNP (rs587780256) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, in ClinVar (classified as likely benign by Ambry Genetics, Color and GeneDx, uncertain significance by Invitae and Counsyl and benign by Integrated Genetics) and LOVD 3.0 (observed 4x). The variant was identified in control databases in 42 of 282,840 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 42 of 129,164 chromosomes (freq: 0.0003); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. In one study in vitro expressio n of the variant had a similar effect on cell survival and RAD51C protein expression compared to wild type (Meindl 2009). The p.Val169 residue is conserved in mammals but not in more distantly related organisms however four out of five 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

Feb 14, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;T;T;T;T

Eigen

Benign

-0.088

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.73

T;T;T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;.;L;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

.;.;N;N;.

REVEL

Benign

0.078

Sift

Benign

0.51

.;.;T;T;.

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

0.0060

.;.;B;.;.

Vest4

0.33, 0.42

MVP

0.77

MPC

0.28

ClinPred

0.094

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.70

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