rs771078849
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_058216.3(RAD51C):āc.622A>Gā(p.Ile208Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000756 in 1,455,756 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I208M) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.622A>G | p.Ile208Val | missense_variant | 4/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.622A>G | p.Ile208Val | missense_variant | 4/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251238Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135782
GnomAD4 exome AF: 0.00000756 AC: 11AN: 1455756Hom.: 0 Cov.: 31 AF XY: 0.00000966 AC XY: 7AN XY: 724578
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2022 | The p.I208V variant (also known as c.622A>G), located in coding exon 4 of the RAD51C gene, results from an A to G substitution at nucleotide position 622. The isoleucine at codon 208 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1/1197 individuals that underwent analysis of 36 genes involved in hereditary cancer predisposition and was classified as a variant of unknown significance (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). 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 | Apr 11, 2023 | This missense variant replaces isoleucine with valine at codon 208 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251238 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 | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31159747, 28678401) - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 208 of the RAD51C protein (p.Ile208Val). This variant is present in population databases (rs771078849, gnomAD 0.003%). This missense change has been observed in individual(s) with RAD51C-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 241773). 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. - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 18, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at