Submissions for variant NM_058216.3(RAD51C):c.716T>A (p.Val239Glu)

dbSNP: rs1064795220

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478142	SCV000570831	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.716T>A at the cDNA level, p.Val239Glu (V239E) at the protein level, and results in the change of a Valine to a Glutamic Acid (GTG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Val239Glu 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 Valine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Val239Glu occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in Walker B box in the ATP binding motif (Miller 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether RAD51C Val239Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001234634	SCV001407290	uncertain significance	Fanconi anemia complementation group O	2022-07-29	criteria provided, single submitter	clinical testing	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 expected to disrupt RAD51C protein function. ClinVar contains an entry for this variant (Variation ID: 421575). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 239 of the RAD51C protein (p.Val239Glu). 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.