Submissions for variant NM_058216.3(RAD51C):c.1005C>A (p.Cys335Ter)

gnomAD frequency: 0.00001  dbSNP: rs759292615

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220031	SCV000275300	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-23	criteria provided, single submitter	clinical testing	The p.C335* variant (also known as c.1005C>A), located in coding exon 8 of the RAD51C gene, results from a C to A substitution at nucleotide position 1005. This changes the amino acid from a cysteine to a stop codon within coding exon 8. This alteration occurs at the 3' terminus of RAD51C gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 11% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232127	SCV000291208	likely pathogenic	Fanconi anemia complementation group O	2022-12-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys335*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the RAD51C protein. This variant is present in population databases (rs759292615, gnomAD 0.006%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys335 amino acid residue in RAD51C. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12966089). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 231450). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions.
GeneDx	RCV000657741	SCV000779492	likely pathogenic	not provided	2020-01-02	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 42 amino acids are lost including the nuclear localization signal (French 2003); Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge