rs750551012
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_058216.3(RAD51C):āc.769C>Gā(p.Leu257Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,612,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000066 ( 0 hom., cov: 30)
Exomes š: 0.0000062 ( 0 hom. )
Consequence
RAD51C
NM_058216.3 missense
NM_058216.3 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 4.31
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_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.321893).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.769C>G | p.Leu257Val | missense_variant | 5/9 | ENST00000337432.9 | NP_478123.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.769C>G | p.Leu257Val | missense_variant | 5/9 | 1 | NM_058216.3 | ENSP00000336701.4 |
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 152056Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251444Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135894
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460020Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 726484
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GnomAD4 genome AF: 0.0000658 AC: 10AN: 152056Hom.: 0 Cov.: 30 AF XY: 0.0000942 AC XY: 7AN XY: 74274
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 29, 2022 | The p.L257V variant (also known as c.769C>G), located in coding exon 5 of the RAD51C gene, results from a C to G substitution at nucleotide position 769. The leucine at codon 257 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 01, 2019 | This missense variant replaces leucine with valine at codon 257 of the RAD51C protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate in vivo binding partner interactions comparable to wild type (Prakash et al., 2022); This variant is associated with the following publications: (PMID: 14704354, 36099300) - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 257 of the RAD51C protein (p.Leu257Val). This variant is present in population databases (rs750551012, gnomAD 0.01%). 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: 232264). 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%. 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.
REVEL
Benign
Sift
Benign
.;T;.
Sift4G
Benign
T;T;D
Polyphen
0.24
.;B;.
Vest4
MutPred
Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);.;
MVP
MPC
0.32
ClinPred
T
GERP RS
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at