17-58694949-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_058216.3(RAD51C):c.164C>T(p.Ala55Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A55T) has been classified as Uncertain significance.
Frequency
Consequence
NM_058216.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.164C>T | p.Ala55Val | missense_variant | 2/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.164C>T | p.Ala55Val | missense_variant | 2/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251206Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461564Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727122
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2022 | The p.A55V variant (also known as c.164C>T), located in coding exon 2 of the RAD51C gene, results from a C to T substitution at nucleotide position 164. The alanine at codon 55 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly 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 | Nov 21, 2023 | This missense variant replaces alanine with valine at codon 55 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant.This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000086). This variant has been identified in 4/282586 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 01, 2022 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer and in unaffected controls (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 35624308, 33471991) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 13, 2018 | - - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 12, 2021 | - - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 55 of the RAD51C protein (p.Ala55Val). This variant is present in population databases (rs730881928, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer (PMID: 28864920). ClinVar contains an entry for this variant (Variation ID: 182831). 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. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 28864920). 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