Submissions for variant NM_058216.3(RAD51C):c.71G>A (p.Arg24Gln)

dbSNP: rs777554369

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220751	SCV000272990	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	clinical testing	The p.R24Q variant (also known as c.71G>A), located in coding exon 1 of the RAD51C gene, results from a G to A substitution at nucleotide position 71. The arginine at codon 24 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not 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.
GeneDx	RCV000590703	SCV000567204	uncertain significance	not provided	2017-02-23	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.71G>A at the cDNA level, p.Arg24Gln (R24Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Arg24Gln 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 Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51C Arg24Gln occurs at a position that is not conserved and is located within the region required for Holliday junction resolution activity (UniProt). 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 Arg24Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000529013	SCV000660415	uncertain significance	Fanconi anemia complementation group O	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the RAD51C protein (p.Arg24Gln). This variant is present in population databases (rs777554369, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 229691). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV000220751	SCV000691264	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590703	SCV000699819	uncertain significance	not provided	2016-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468978	SCV004207969	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-08-06	criteria provided, single submitter	clinical testing