rs730881925
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The ENST00000337432.9(RAD51C):c.746G>A(p.Arg249His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,458,812 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R249C) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000337432.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.746G>A | p.Arg249His | 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.746G>A | p.Arg249His | missense_variant | 5/9 | 1 | NM_058216.3 | ENSP00000336701 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 151796Hom.: 0 Cov.: 30 FAILED QC
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251434Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135888
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1458812Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 20AN XY: 725940
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 151796Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74090
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Nov 22, 2019 | This variant has been reported in the literature in an individual with breast cancer (Lu 2015). This variant has an overall allele frequency of 0.000016 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.746G>A (p.Arg249His) has been reported in an individual with breast cancer, as well as an unaffected control individual (Lu C et al., 2015). This missense variant has been submitted to ClinVar as a Variant of Uncertain Significance. The p.Arg249His variant is is observed in 0.001% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 249 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg249His in RAD51C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2022 | This missense variant replaces arginine with histidine at codon 249 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 observed in an individual affected with breast cancer (PMID: 26689913) and in a control individual from an ovarian cancer case-control study (PMID: 26261251). In a large breast cancer case-control study, this variant was observed in 1/60466 cases and 2/53461 unaffected controls (OR=0.442, 95%CI 0.04 to 4.876, p-value=0.603) (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000187). This variant has also been identified in 5/251434 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 | Ambry Genetics | Nov 18, 2022 | The p.R249H variant (also known as c.746G>A), located in coding exon 5 of the RAD51C gene, results from a G to A substitution at nucleotide position 746. The arginine at codon 249 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was not observed in 3429 patients with invasive epithelial ovarian cancer, but was reported in 1/2722 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This variant has also been reported in a patient with breast cancer (Lu C et al. Nat. Commun. 2015 Dec;6:10086). 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 alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2018 | Variant summary: RAD51C c.746G>A (p.Arg249His) results in a non-conservative amino acid change located in the C-terminal of the Rad51-like DNA recombination and repair protein domain and the RecA-like DNA recombination and repair protein ATP-binding domain. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 2e-05 in 255756 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in RAD51C causing Hereditary Breast and Ovarian Cancer (2e-05 vs 6.3e-05), allowing no conclusion about variant significance. The variant, c.746G>A, has been reported in the literature in a cohort of cancer cases (specific phenotype not provided; Lu_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 07, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect on RAD51D, RAD51B, and XRCC3 interactions (PMID: 36099300); This variant is associated with the following publications: (PMID: 26261251, 33471991, 26689913, 14704354, 25085752, 36099300) - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 249 of the RAD51C protein (p.Arg249His). This variant is present in population databases (rs730881925, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 26261251, 26689913). ClinVar contains an entry for this variant (Variation ID: 182828). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51C protein function. 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