rs587780255

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_058216.3(RAD51C):c.428A>G(p.Gln143Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,102 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q143E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11

Conservation

PhyloP100: 8.24

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_058216.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.428A>G	p.Gln143Arg	missense_variant	3/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.428A>G	p.Gln143Arg	missense_variant	3/9	1	NM_058216.3	P2	O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251480

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135912

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:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Likely pathogenic, flagged submission	curation	Leiden Open Variation Database	Nov 02, 2014	Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2023	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: 25086635, 26740214, 27622768, 28829762, 28873162, 24993905, 24800917, 25154786, 25470109, 22538716, 26261251, 25292178, 21537932, 22451500, 26720728, 26976419, 23117857, 29409816, 29522266, 29641532, 32008151, 14704354, 36099300, 33359728, 35039523) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2022	In the published literature, this variant has been reported in in individuals/families with breast and/or ovarian cancer as well as in unaffected controls (PMIDs: 21537932 (2011), 22538716 (2012), 24993905 (2014), 26261251 (2015), 26720728 (2016), 26976419 (2016), 26740214 (2016), 27622768 (2017), 33471991 (2021), 35039523 (2022), see also LOVD (http://databases.lovd.nl/shared/genes/ RAD51C). Functional studies were inconclusive regarding the effect of this variant on RAD51C protein function (PMIDs: 22451500 (2012), 25292178 (2015), 36099300 (2022), 35039523 (2022), and 37253112 (2023)). The frequency of this variant in the general population, 0.000079 (9/113756 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 20, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces glutamine with arginine at codon 143 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant partially impairs RAD51 foci formation, homologous recombination and cell cycle control (PMID: 22451500, 25292178) and results in reduced RAD51C binding to RAD51B, RAD51D and XRCC3 (PMID: 36099300). This variant has been reported in three individuals affected with ovarian cancer (PMID: 26261251, 26720728, 35039523) and over ten individuals with breast cancer (PMID: 21537932, 22451500, 22538716, 24993905, 26740214, 26976419, 27622768, 35039523). In a familial breast cancer case-control study, this variant has been identified in 4/5,734 cases and 3/14,382 controls (PMID: 35039523). This variant has been identified in 9/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in dozens of individuals lacking a personal history of ovarian or breast cancer (Color internal data). 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 29, 2023	The p.Q143R variant (also known as c.428A>G), located in coding exon 3 of the RAD51C gene, results from an A to G substitution at nucleotide position 428. The glutamine at codon 143 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in 2/6237 ovarian cancer patients and 1/5084 healthy control individuals across multiple studies (Loveday C et al. Nat. Genet. 2012 May;44:475-6; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). In another study, this alteration was reported in 0.07% (4/ 5,734) hereditary breast and ovarian cancer families and 0.02% (3/4,382) cancer-free female controls (Lim BWX et al. NPJ Breast Cancer, 2022 Jan;8:10). Further, this variant has been detected in multiple breast cancer patients (Romero A et al. Breast Cancer Res. Treat. 2011 Oct;129:939-46; Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). One functional study revealed that RAD51C-deficient cells transfected with this variant were unable to restore RAD51C foci-formation to levels comparable to wild type (less than 50% of wild type foci-formation) (Osorio A et al. Hum. Mol. Genet. 2012 Jul;21:2889-98). 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. -

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Dr. med. U. Finckh, Human Genetics, Eurofins MVZ	Sep 01, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 06, 2020

DNA sequence analysis of the RAD51C gene demonstrated a sequence change, c.428A>G, in exon 3 that results in an amino acid change, p.Gln143Arg. This sequence change has been described in the gnomAD database with a frequency of 0.008% in the European sub-population (dbSNP rs587780255). The p.Gln143Arg change has been reported in individuals with breast or ovarian cancer and a breast cancer family, however co-segregation studies were not performed (PMID: 22451500, 22538716, 21537932, 26976419, 26720728, 26740214). The p.Gln143Arg change affects a highly conserved amino acid residue located in a domain of the RAD51C protein that is known to be functional. The p.Gln143Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies demonstrated reduced protein activity, reduced homologous recombination activity, increased sensitivity to PARP inhibitors, and failure to suppress cell cycle accumulation compared to the wild-type protein (PMIDs: 22451500, 25292178). Due to insufficient evidence, the clinical significance of the p.Gln143Arg change remains unknown at this time. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 15, 2018

- -

RAD51C-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2023

The RAD51C c.428A>G variant is predicted to result in the amino acid substitution p.Gln143Arg. This variant has been reported in individuals with a history of breast and ovarian cancer (Osorio et al. 2012. PubMed ID: 22451500; Supplementary Table 3, Loveday et al. 2012. PubMed ID: 22538716; Figure S4, Romero et al. 2011. PubMed ID: 21537932; Table A2, Tung et al. 2016. PubMed ID: 26976419; Table 1, Gevensleben et al. 2014. PubMed ID: 24993905; Table A3, Song et al. 2015. PubMed ID: 26261251; Norquist et al. 2016. PubMed ID: 26720728; Neidhardt et al. 2017. PubMed ID: 27622768). In at least one family study, this variant segregated with breast cancer in an individual who inherited the variant from her affected mother. However, in the same family an unaffected maternal aunt was positive for the same variant (Figure 1B, Jønson et al. 2016. PubMed ID: 26740214). It has been reported in cases and controls from a breast cancer cohort study (Table S1, Lim et al. 2022. PubMed ID: 35039523). Functional studies of the RAD51C protein suggest this variant impacts protein activity (Osorio et al. 2012. PubMed ID: 22451500), specifically homologous recombination, sensitivity to polymerase inhibitors, and cell cycle function (Somyajit et al. 2015. PubMed ID: 25292178). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56774077-A-G) and is interpreted as uncertain significance by the vast majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/128205/). Although we suspect that this variant may be pathogenic, 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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 143 of the RAD51C protein (p.Gln143Arg). This variant is present in population databases (rs587780255, gnomAD 0.008%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 21537932, 22451500, 22538716, 26720728, 26740214, 26976419). ClinVar contains an entry for this variant (Variation ID: 128205). 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 RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 22451500, 25292178). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;T;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Benign

-0.43

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.94

.;.;P;.;.

Vest4

0.97, 0.97

MutPred

0.81

.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;

MVP

0.77

MPC

0.75

ClinPred

0.93

GERP RS

5.7

Varity_R

0.78

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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