Submissions for variant NM_058216.3(RAD51C):c.705+1G>A

dbSNP: rs876658644

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218961	SCV000274169	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-10-26	criteria provided, single submitter	clinical testing	The c.705+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the RAD51C gene. This variant has been reported in individuals with breast cancer and/or ovarian cancer (Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90; Li N et al. J Natl Cancer Inst, 2019 Dec;111:1332-1338; Yang X et al. J Natl Cancer Inst, 2020 Dec;112:1242-1250). 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. In a functional RNA study, this variant was associated with exon 4 skipping (Sanoguera-Miralles L et al. Cancers (Basel), 2022 Jun;14: 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.
Color Diagnostics, LLC DBA Color Health	RCV000218961	SCV000686373	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26720728, 30949688, 32107557). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648247	SCV000770061	pathogenic	Fanconi anemia complementation group O	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered 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 and/or ovarian cancer (PMID: 26720728, 30949688, 32107557). ClinVar contains an entry for this variant (Variation ID: 230577). 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; internal data). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503867	SCV002812633	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2024-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004020657	SCV004931161	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-03	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.