Submissions for variant NM_058216.3(RAD51C):c.1108C>T (p.Arg370Ter)

gnomAD frequency: 0.00006  dbSNP: rs756744016

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167018	SCV000217841	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	The p.R370* variant (also known as c.1108C>T) located in coding exon 9 of the RAD51C gene, results from a C to T substitution at nucleotide position 1108. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration was detected in a cohort of 116 patients from Chinese familial breast cancer families (Dong L et al. Cancer Biol Med, 2021 Sep;19:850-70). This alteration occurs at the 3' terminus of the RAD51C gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last seven amino acids of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000237017	SCV000292883	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 4 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 12966089, 14704354, 37298034, 34570441, 32809180, 35171259)
Invitae	RCV000559698	SCV000650004	uncertain significance	Fanconi anemia complementation group O	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg370*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the RAD51C protein. This variant is present in population databases (rs756744016, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 32809180, 34570441). ClinVar contains an entry for this variant (Variation ID: 187300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000167018	SCV001348286	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the RAD51C gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape nonsense-mediated decay, it is expected to delete 7 amino acids from the C-terminus of the RAD51C protein. While to our knowledge, functional studies have not been reported for this variant, cells with a variant protein missing the 11 amino acids from the C-terminus have been reported to have reduced mitomycin C resistance (PMID: 12966089). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/280040 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.
Baylor Genetics	RCV003468797	SCV004207989	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-06-22	criteria provided, single submitter	clinical testing