Submissions for variant NM_058216.3(RAD51C):c.965+1G>A

dbSNP: rs730881933

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160926	SCV000211630	likely pathogenic	not provided	2017-09-06	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.965+1G>A or IVS7+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 7 of the RAD51C gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been observed in an individual with breast cancer (Susswein 2016). Based on the current evidence, we consider RAD51C c.965+1G>A to be likely pathogenic.
Invitae	RCV000698614	SCV000827290	pathogenic	Fanconi anemia complementation group O	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182838). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 35740625; Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001183046	SCV001348696	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with breast cancer (PMID: 26681312). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001183046	SCV002694201	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	The c.965+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the RAD51C gene. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel. (Susswein LR et al. Genet Med, 2016 08;18:823-32). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV003467270	SCV004208063	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2021-01-06	criteria provided, single submitter	clinical testing