17-58709931-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_058216.3(RAD51C):​c.778C>T​(p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,242 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

4
12
3

Clinical Significance

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

Conservation

PhyloP100: 0.884
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD51CNM_058216.3 linkc.778C>T p.Arg260Trp missense_variant 5/9 ENST00000337432.9 NP_478123.1 O43502-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD51CENST00000337432.9 linkc.778C>T p.Arg260Trp missense_variant 5/91 NM_058216.3 ENSP00000336701.4 O43502-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152042
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000725
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251438
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
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:
0.00000479
AC:
7
AN:
1460200
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726554
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152042
Hom.:
0
Cov.:
30
AF XY:
0.0000135
AC XY:
1
AN XY:
74258
show subpopulations
Gnomad4 AFR
AF:
0.0000725
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 01, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 28, 2017Variant summary: The RAD51C c.778C>T (p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 2/121402 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant was found in one CRC patient in one study without strong evidence for causality (Yurgelun_CDH1_JCO_2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 10, 2024Not 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; Observed in an individual with colorectal cancer (PMID: 28135145); This variant is associated with the following publications: (PMID: 31159747, 14704354, 37253112, 28135145, 36099300) -
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneKor MSAAug 01, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 13, 2024The p.R260W variant (also known as c.778C>T), located in coding exon 5 of the RAD51C gene, results from a C to T substitution at nucleotide position 778. The arginine at codon 260 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 13, 2020This missense variant replaces arginine with tryptophan at codon 260 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 2/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsOct 17, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMJul 22, 2023The missense variant c.778C>Tp.Arg260Trp in RAD51C gene has been reported in individuals affected with RAD51C related disorders Yurgelun et. al., 2017; Tsaousis et. al., 2019, The observed variant has allele frequency of 0.0008% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance multiple submitters. Multiple lines of computational evidence Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg260Trp in RAD51C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 260 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance VUS. -
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 23, 2024- -
RAD51C-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 23, 2024The RAD51C c.778C>T variant is predicted to result in the amino acid substitution p.Arg260Trp. This variant has been reported in an individual with colorectal cancer and an individual undergoing genetic testing for hereditary cancer predisposition syndromes (Table A4. Yurgelun et al 2017. PubMed ID: 28135145; Table S5. Tsaousis et al 2019. PubMed ID: 31159747). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141175/). 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2025This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 260 of the RAD51C protein (p.Arg260Trp). This variant is present in population databases (rs374196453, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and an individual undergoing genetic testing for hereditary cancer predisposition (PMID: 28135145, 31159747). ClinVar contains an entry for this variant (Variation ID: 141175). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on RAD51C function (PMID: 37253112). 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
Uncertain
0.46
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.11
T;T;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.9
.;M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-5.7
.;D;.
REVEL
Uncertain
0.60
Sift
Uncertain
0.0010
.;D;.
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.79
MVP
0.89
MPC
0.86
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.86
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.

Other links and lift over

dbSNP: rs374196453; hg19: chr17-56787292; API