17-58709883-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_058216.3(RAD51C):c.730A>G(p.Ile244Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000739 in 1,609,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. I244F) has been classified as Uncertain significance.
Frequency
Consequence
NM_058216.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.730A>G | p.Ile244Val | missense_variant | 5/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.730A>G | p.Ile244Val | missense_variant | 5/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152070Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251422Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135886
GnomAD4 exome AF: 0.0000789 AC: 115AN: 1457570Hom.: 0 Cov.: 30 AF XY: 0.0000772 AC XY: 56AN XY: 725500
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152188Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 4AN XY: 74426
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 01, 2016 | Variant summary: The RAD51C c.730A>G (p.Ile244Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 6/123714 control chromosomes at a frequency of 0.0000485, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). The variant has been reported in the literature as absent in an ovarian cancer cohort but was found once in controls (Loveday_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2023 | Observed in individuals with breast/ovarian or colon cancers (Tung et al. 2015, Pearlman et al. 2017, Kadri et al. 2020; Lim et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22538716, 25186627, 33552952, 25470109, 27978560, 14704354, 35039523) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2023 | In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 27978560 (2016)), breast cancer (PMID: 25186627 (2015), 33552952 (2020)) and in unaffected individuals (PMID: 22538716 (2016)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). The frequency of this variant in the general population, 0.00023 (7/30612 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2022 | The p.I244V variant (also known as c.730A>G), located in coding exon 5 of the RAD51C gene, results from an A to G substitution at nucleotide position 730. The isoleucine at codon 244 is replaced by valine, an amino acid with highly similar properties. In one UK study, this variant was seen in 1/2312 controls but not in 2808 ovarian cancer cases (Loveday C et al Nat. Genet. 2012 Apr;44:475-6). It was also reported in 1/450 patients with colorectal cancer diagnosed under the age of 50, who underwent a 25 gene panel test (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). The alteration was also detected in a cohort of 144 Indian patients with a personal and/or family history of breast and/or ovarian cancer (Kadri MSN et al. Front Oncol, 2020 Jan;10:568786). 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 | Mar 07, 2023 | This missense variant replaces isoleucine with valine at codon 244 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 been reported in individuals affected with hereditary breast and ovarian cancer (PMID: 33552952), breast cancer (PMID: 25186627) and colorectal cancer (PMID: 27978560), as well as in a healthy control individual (PMID: 22538716). This variant has been identified in 12/251422 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. - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | This sequence change replaces isoleucine with valine at codon 244 of the RAD51C protein (p.Ile244Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 182827) with 5 submission, all of which describe it as of uncertain significance, two stars, no conflicts. In-silico predictions show this variant is likely to be tolerated. However, these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
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 | Mar 22, 2022 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 21, 2023 | - - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 244 of the RAD51C protein (p.Ile244Val). This variant is present in population databases (rs199886026, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 182827). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at