Submissions for variant NM_058216.3(RAD51C):c.1006A>C (p.Thr336Pro)

gnomAD frequency: 0.00003  dbSNP: rs772344354

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461973	SCV000550178	uncertain significance	Fanconi anemia complementation group O	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 336 of the RAD51C protein (p.Thr336Pro). This variant is present in population databases (rs772344354, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 26261251, 34326862). ClinVar contains an entry for this variant (Variation ID: 409832). 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%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 37253112). 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.
GeneDx	RCV000477986	SCV000565461	uncertain significance	not provided	2018-11-14	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.1006A>C at the cDNA level, p.Thr336Pro (T336P) at the protein level, and results in the change of a Threonine to a Proline (ACA>CCA). This variant has been observed in at least one individual with epithelial ovarian cancer (Song 2015). RAD51C Thr336Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region interaction with RAB51B, RAD51D,XRCC3 (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Thr336Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000564945	SCV000671882	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-31	criteria provided, single submitter	clinical testing	The p.T336P variant (also known as c.1006A>C), located in coding exon 8 of the RAD51C gene, results from an A to C substitution at nucleotide position 1006. The threonine at codon 336 is replaced by proline, an amino acid with highly similar properties. This variant has been reported in 1/3,429 patients with invasive epithelial ovarian cancer (EOC) and was not seen in any of the 2,772 controls or 2,000 additional unaffected women who were BRCA1/BRCA2 mutation-negative (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). In a homology-directed DNA repair (HDR) assay, this alteration showed a functionally abnormal read-out; however, in a PARP inhibitor and cisplatin sensitivity assay, this alteration showed a functionally indeterminant read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000564945	SCV000691211	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 336 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 been reported in an individual affected with ovarian cancer (PMID: 26261251). This variant has also been identified in 3/282810 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.