rs773998134
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_058216.3(RAD51C):c.106G>A(p.Glu36Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. E36G) has been classified as Benign.
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.106G>A | p.Glu36Lys | missense_variant | 1/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.106G>A | p.Glu36Lys | missense_variant | 1/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251458Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 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; This variant is associated with the following publications: (PMID: 22451500, 25470109, 23117857, 21537932, 24139550, 34923718, 29484706) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 15, 2023 | In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 29484706 (2018), 24139550 (2013), 23117857 (2012), 21537932 (2011)). A published functional study reported that this variant does not significantly disrupt homology direct repair activity (PMID: 37253112 (2023)). The frequency of this variant in the general population, 0.000035 (4/113752 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The p.E36K variant (also known as c.106G>A), located in coding exon 1 of the RAD51C gene, results from a G to A substitution at nucleotide position 106. The glutamic acid at codon 36 is replaced by lysine, an amino acid with similar properties. This alteration was originally identified in a Spanish female diagnosed with breast cancer at age 38 who had two relatives with breast cancer (Romero A et al. Breast Cancer Res. Treat. 2011 Oct;129(3):939-46). This cohort was later included with other Spanish breast and/or ovarian cancer families, and p.E36K was ultimately reported in 1/785 affected families (Osorio A et al. Hum. Mol. Genet. 2012 Jul;21(13):2889-98). This variant was also reported in 2/142 unrelated patients with breast and/or ovarian cancer who had either early onset cancer or a family history of breast/ovarian cancer (Goldmar L et al. BMC Cancer. 2013;13:484), and also reported in 1/34 Italian breast cancer patients (Guacci A et al. J Clin Lab Anal, 2018 Jul;32:e22418). In a homology-directed DNA repair (HDR) assay, this alteration showed a functionally normal read-out. (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is well 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 03, 2021 | - - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 36 of the RAD51C protein (p.Glu36Lys). This variant is present in population databases (rs773998134, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 34923718). ClinVar contains an entry for this variant (Variation ID: 216803). 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. 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 | Mar 13, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at