17-58696746-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_058216.3(RAD51C):c.458G>A(p.Gly153Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G153G) has been classified as Likely benign.
Frequency
Consequence
NM_058216.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.458G>A | p.Gly153Asp | missense_variant | 3/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.458G>A | p.Gly153Asp | missense_variant | 3/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251462Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:3
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Nov 02, 2014 | Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2016 | This variant is denoted RAD51C c.458G>A at the cDNA level, p.Gly153Asp (G153D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant was observed in an individual with breast and ovarian cancer, and functional study demonstrated loss of interaction with XRCC3 and RAD51B (Clague 2011). RAD51C Gly153Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Gly153Asp occurs at a position that is conserved across species and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider RAD51C Gly153Asp to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2016 | Variant summary: The c.458G>A (p.Gly153Asp) in RAD51C gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is located outside of any known functional domain. Yet, functional studies have shown that this missense change alters the ability of RAD51C protein to form a complex with XRCC1 and RAD51B. (Clague, 2011). The variant is present in the large control population dataset of ExAC at a low frequency 0.000008 (1/121372 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.00006) in this gene. The variant has been reported in at least 1 affected individuals in the literature without segregation analysis being performed. In addition, several reputable databases/clinical laboratories classify the variant as VUS. Lastly, this variant was identified in an internal specimen undergoing genetic testing together with c.1100delC in CHEK2 gene. Taken together, the variant was classified as VUS until more data become available. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2022 | The p.G153D variant (also known as c.458G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 458. The glycine at codon 153 is replaced by aspartic acid, an amino acid with similar properties. This alteration has previously been reported in an individual diagnosed with breast cancer at age 60 and ovarian cancer at age 79. Functional analyses of this alteration showed little effect on RAD51C protein expression (immunoblot assay); however, it disrupted the interaction between RAD51C and RAD51B and XRCC3 in yeast two-hybrid assays (Clague J, PLoS ONE 2011 ; 6(9):e25632). 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 variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 03, 2019 | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 19, 2022 | DNA sequence analysis of the RAD51C gene demonstrated a sequence change, c.458G>A, in exon 3 that results in an amino acid change, p.Gly153Asp. This sequence change has been previously described in an individual with breast and ovarian cancer (PMID: 21980511). Functional assays showed that this variant alters the ability of RAD51C to interact with XRCC3 and RAD51B but no significant impact on RAD51C protein expression (PMID: 21980511). This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.0008% (dbSNP rs765730332). The p.Gly153Asp change affects a highly conserved amino acid residue located in a domain of the RAD51C protein that is known to be functional. The p.Gly153Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences the clinical significance of the p.Gly153Asp change remains unknown at this time. - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 153 of the RAD51C protein (p.Gly153Asp). This variant is present in population databases (rs765730332, gnomAD 0.003%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21980511). ClinVar contains an entry for this variant (Variation ID: 185444). 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 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: 21980511). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at