rs1555594725
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_058216.3(RAD51C):c.482A>T(p.Glu161Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,870 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: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
RAD51C
NM_058216.3 missense
NM_058216.3 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 6.37
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.482A>T | p.Glu161Val | missense_variant | 3/9 | ENST00000337432.9 | NP_478123.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.482A>T | p.Glu161Val | missense_variant | 3/9 | 1 | NM_058216.3 | ENSP00000336701.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 exome
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5
AN:
1461870
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31
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2
AN XY:
727236
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
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EpiControl
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2016 | Variant summary: The c.482A>T (p.Glu161Val) in RAD51C gene is a missense change that involves a highly conserved nucleotide and 4/5 in silico tools predict damaging outcome. The variant of interest is located within a functional domain required for DNA recombination, and mutations in this region found in HBOC pts were presumably associated with RAD51C-mediated breast and ovarian cancer. The variant is absent from the control population dataset of ExAC and has not, to our knowledge, been reported in affected individuals via published reports or by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2021 | The p.E161V variant (also known as c.482A>T), located in coding exon 3 of the RAD51C gene, results from an A to T substitution at nucleotide position 482. The glutamic acid at codon 161 is replaced by valine, an amino acid with dissimilar properties. This alteration has been identified in a breast and/or ovarian cancer patient (Van Marcke C et al. Breast Cancer Res, 2020 04;22:36). 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. - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 161 of the RAD51C protein (p.Glu161Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 496504). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51C protein function. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;D;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;H;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;D;.
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
1.0
.;.;D;.;.
Vest4
0.68, 0.71
MutPred
0.90
.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;
MVP
MPC
0.90
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at