Submissions for variant NM_058216.3(RAD51C):c.395C>G (p.Thr132Arg)

dbSNP: rs730881930

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160922	SCV000211626	uncertain significance	not provided	2016-11-29	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.395C>G at the cDNA level, p.Thr132Arg (T132R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Thr132Arg 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 Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51C Thr132Arg occurs at a position that is conserved across species and is located within an ATPase motif and the region of interaction with RAD51B, RAD51D, and XRCC3 (French 2003, Miller 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51C Thr132Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206110	SCV000261074	uncertain significance	Fanconi anemia complementation group O	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 132 of the RAD51C protein (p.Thr132Arg). 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: 182834). 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 with a positive 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.
Ambry Genetics	RCV000218584	SCV000276270	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The p.T132R variant (also known as c.395C>G), located in coding exon 2 of the RAD51C gene, results from a C to G substitution at nucleotide position 395. The threonine at codon 132 is replaced by arginine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000218584	SCV000909440	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798558	SCV002043688	uncertain significance	Breast and/or ovarian cancer	2019-11-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467268	SCV004207918	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467268	SCV004932173	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-02-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 37253112]. This variant is expected to disrupt protein structure [Myriad internal data].