Submissions for variant NM_058216.3(RAD51C):c.696A>T (p.Glu232Asp)

dbSNP: rs786201177

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222399	SCV000276506	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-18	criteria provided, single submitter	clinical testing	The p.E232D variant (also known as c.696A>T), located in coding exon 4 of the RAD51C gene, results from an A to T substitution at nucleotide position 696. The glutamic acid at codon 232 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000480805	SCV000571576	uncertain significance	not provided	2017-11-09	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.696A>T at the cDNA level, p.Glu232Asp (E232D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Glu232Asp was not observed in large population cohorts (Lek 2016). Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. RAD51C Glu232Asp is located within the region of interaction with RAD51B, RAD51D, XRCC3 (Miller 2004). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Glu232Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000222399	SCV000904874	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 232 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219422	SCV001391359	uncertain significance	Fanconi anemia complementation group O	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 232 of the RAD51C protein (p.Glu232Asp). This variant is not present in population databases (gnomAD no frequency). 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: 232379). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Fulgent Genetics, Fulgent Genetics	RCV002485424	SCV002793183	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2024-06-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532794	SCV004108529	uncertain significance	RAD51C-related disorder	2023-07-06	criteria provided, single submitter	clinical testing	The RAD51C c.696A>T variant is predicted to result in the amino acid substitution p.Glu232Asp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is classified as having uncertain clinical significance by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/232379/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.