rs587781921
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_058216.3(RAD51C):c.620A>G(p.His207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,608,134 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 (★★).
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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000687 AC: 10AN: 1455968Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 6AN XY: 724710
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The c.620A>G (p.H207R) alteration is located in exon 4 (coding exon 4) of the RAD51C gene. This alteration results from a A to G substitution at nucleotide position 620, causing the histidine (H) at amino acid position 207 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
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Breast and/or ovarian cancer Uncertain:1
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not provided Uncertain:1
This variant is denoted RAD51C c.620A>G at the cDNA level, p.His207Arg (H207R) at the protein level, and results in the change of a Histidine to a Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. RAD51C His207Arg occurs at a position that is conserved in mammals and is located within the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51C His207Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Fanconi anemia complementation group O Uncertain:1
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 207 of the RAD51C protein (p.His207Arg). This variant is present in population databases (rs587781921, gnomAD 0.007%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 141663). 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at