rs267606997

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_058216.3(RAD51C):c.773G>A(p.Arg258His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,611,850 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 7.47

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 Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 17-58709926-G-A is Pathogenic according to our data. Variant chr17-58709926-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58709926-G-A is described in Lovd as [Pathogenic]. Variant chr17-58709926-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.773G>A	p.Arg258His	missense_variant	Exon 5 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.773G>A	p.Arg258His	missense_variant	Exon 5 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251428

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135886

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1459932

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726444

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:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group O

Pathogenic:5

Aug 11, 2010

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fanconi anaemia, complementation group O (MIM#613390). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Multiple alternative changes at this location have been reported as VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in ClinVar. It has also been reported in a consanguineous family with fanconi anaemia (PMID: 20400963). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity (PMID: 20400963). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RAD51C protein (p.Arg258His). This variant is present in population databases (rs267606997, gnomAD 0.003%). This missense change has been observed in individuals with breast and/or ovarian cancer and features of Fanconi anemia (PMID: 20400963, 25154786, 26740214, 32054657, 32242007). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6822). 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 expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 20400963, 22167183, 26354865). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3Uncertain:1

Dec 18, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PP1 c.773G>A, located in exon 5 of the RAD51C gene, is predicted to result in the substitution of arginine by histidine at codon 258, p.(Arg258His). This variant is found in 4/102712 alleles at a frequency of 0.0038% within the European (non-Finnish) population in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.497) for this variant is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). This variant has been reported in homozygosity in two pediatric siblings showing features of Fanconi anemia (PMID: 20400963) (PM3, PP1). Functional studies have shown that the mutant protein shows a reduced DNA damage response in transduced primary fibroblasts from a FA patient carrying the variant in homozygous and in the chicken ΔRAD51C-DT40 cell line, but in another cell line, the hamster cell line irs3, there was some evidence suggesting the variant is a hypomorphic mutant as some residual RAD51C function may be reserved (PMID: 20400963, 20952512). This variant has been reported in the ClinVar database (7x likely pathogenic, 5x pathogenic) and in the LOVD database (1x likely pathogenic, 7x pathogenic). Based on the currently available information, c.773G>A is classified as an uncertain significance variant according to ACMG guidelines. -

Oct 02, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R258H variant (also known as c.773G>A), located in coding exon 5 of the RAD51C gene, results from a G to A substitution at nucleotide position 773. The arginine at codon 258 is replaced by histidine, an amino acid with highly similar properties. In one Pakistani family, two siblings affected with Fanconi anemia-like disorder were both homozygous for this alteration, while their consanguineous parents were both heterozygous for this alteration and an unaffected sibling was homozygous for the wild type allele (Vaz F et al. Nat. Genet. 2010 May; 42(5):406-9). Multiple functional studies on this alteration have demonstrated impaired protein function, with some evidence suggesting it is a hypomorphic mutant as some residual RAD51C function may be reserved (Vaz F et al. Nat. Genet. 2010 May; 42(5):406-9; Somyajit K et al. Carcinogenesis. 2010 Dec; 31(12):2031-8; Somyajit K et al. J. Biol. Chem. 2012 Jan; 287(5):3366-80;Park JY et al. Oncogene, 2014 Oct;33:4803-12). This alteration has also been reported in cohorts of individuals with increased risk of hereditary breast and/or ovarian cancer (Jønson L et al. Breast Cancer Res. Treat. 2016 Jan; 155(2):215-22; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Subramanian DN et al. Nat Commun, 2020 04;11:1640). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3; PS3_MOD; PS4_SUP; PP1. The variant may have reduced penetranse (Hypomorphic) -

Sep 14, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 258 in the RAD51B/RAD51D/ XRCC3 interacting domain of the RAD51C protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Functional studies have shown that the mutant protein shows a reduced DNA damage response (PMID: 20400963, 22167183) and reduced ability to bind to other proteins involved in DNA repair (PMID 22167183, 24141787). This variant has been reported in homozygosity in two pediatric siblings and an adult individual showing features of Fanconi anemia (PMID: 20400963, 32054657). This variant has also been observed in an individual affected with familial ovarian cancer (PMID: 32242007) and breast and/or ovarian cancer (PMID: 26740214), as well as in an unaffected individual (PMID 25154786). This variant has been identified in 4/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:2

Dec 05, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 31742824, 32242007, 35039523, 37444530); Published functional studies suggest a damaging effect: failure to protect replication forks, moderately suppressed G2/M accumulation, partial loss of homologous recombination activity and DNA interstrand cross-link repair, reduced RAD51 foci formation, and decreased binding affinity (PMID: 22167183, 25292178, 26354865, 36099300, 37253112, 37488098); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26103414, 20400964, 25833843, 20952512, 21821141, 22167183, 26354865, 20400963, 27037238, 20428093, 26740214, 29278735, 25154786, 29922827, 22451500, 24141787, 28152038, 31589614, 31742824, 32338768, 32090079, 33015624, 32054657, 33804961, 34910513, 30551670, 35039523, 32242007, 37444530, 25292178, 36099300, 37253112, 37488098, 28829762, 27149842, 24998779, 36562461, 35740625, 14704354, 34887416, 36906610) -

Jul 21, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:2

Mar 10, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20400963, 32054657]. Functional studies indicate this variant impacts protein function [PMID: 20400963, 36099300, 22167183, 26354865, 24141787]. -

Feb 22, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Nov 05, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAD51C c.773G>A (p.Arg258His) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal (IPR013632) 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 1.6e-05 in 251428 control chromosomes (gnomAD). c.773G>A has been reported in the literature as a biallelic mutation in multiple individuals from a family affected with Fanconi-anemia-like disorder (Vaz_2010). The variant has also been reported in at least one patient with breast cancer family history, although this patient also had a co-occurring mutation in BRCA2 that was predicted by the authors to be pathogenic (Ahlborn_2014, Jonson_2016). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. Cells expressing the variant protein were shown to have decreased formation of RAD51 foci in response to DNA damage (Vaz_2010), a reduction in binding to other proteins in a complex with BRCA2, PALB2, and RAD51 (Park_2014) and impaired replication fork maintenance (Somyajit_2015). Collectively, these data indicate that the variant results in an impaired ability to repair DNA damage. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

T;T;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Pathogenic

3.7

.;H;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.1

.;D;.

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.91

MutPred

0.96

Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);.;

MVP

0.94

MPC

0.94

ClinPred

1.0

GERP RS

6.0

Varity_R

0.92

gMVP

0.83

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