Submissions for variant NM_058216.3(RAD51C):c.115C>G (p.Leu39Val)

dbSNP: rs759149207

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164977	SCV000215670	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-05	criteria provided, single submitter	clinical testing	The p.L39V variant (also known as c.115C>G), located in coding exon 1 of the RAD51C gene, results from a C to G substitution at nucleotide position 115. The leucine at codon 39 is replaced by valine, an amino acid with highly similar properties. 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.
Counsyl	RCV000409780	SCV000489887	uncertain significance	Fanconi anemia complementation group O	2016-07-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000411003	SCV000489888	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-07-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000484927	SCV000565457	uncertain significance	not provided	2014-10-17	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.115C>G at the cDNA level, p.Leu39Val (L39V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Leu39Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. RAD51C Leu39Val occurs at a position that is moderately conserved across species and is located in the region required for Holliday junction resolution activity (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether RAD51C Leu39Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000409780	SCV000812409	uncertain significance	Fanconi anemia complementation group O	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 39 of the RAD51C protein (p.Leu39Val). This variant is present in population databases (rs759149207, gnomAD 0.0009%). 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: 185535). 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.
Color Diagnostics, LLC DBA Color Health	RCV000164977	SCV000909435	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 39 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 been identified in 1/251416 chromosomes 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.
Myriad Genetics, Inc.	RCV000411003	SCV004019917	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.