Submissions for variant NM_058216.3(RAD51C):c.837+1G>C

dbSNP: rs760235677

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199931	SCV001370714	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-11	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.837+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251374 control chromosomes (gnomAD). To our knowledge, no occurrence of c.837+1G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378839	SCV001576516	pathogenic	Fanconi anemia complementation group O	2022-02-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 21616938). ClinVar contains an entry for this variant (Variation ID: 932211). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21616938, 25470109, 28802053, 30927251, 32107557). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917).
Ambry Genetics	RCV003163504	SCV003861281	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The c.837+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 5 of the RAD51C gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Drexler GA et al. DNA Repair (Amst.) 2004 Oct;3(10):1335-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003163504	SCV004357129	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +1 position of intron 5 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 not been reported in individuals affected with RAD51C-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Another variant affecting the same splice site, c.837+1G>A, has been detected in individuals affected with breast and/or ovarian cancer (ClinVar Variation ID: 229854). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV004033484	SCV004933479	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.
Laboratory for Genotyping Development, RIKEN	RCV003163505	SCV002758220	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research