ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.706-1G>A

dbSNP: rs1555599090
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Hereditary Cancer Group, L’Institut d'Investigació Biomèdica de Bellvitge RCV001779207 SCV001623542 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2021-05-10 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV001859339 SCV002316447 pathogenic Fanconi anemia complementation group O 2022-10-28 criteria provided, single submitter clinical testing Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 22006311, 24139550; Invitae). This variant disrupts a region of the RAD51C protein in which other variant(s) (p.Arg258His) have been determined to be pathogenic (PMID: 20400963, 22167183, 26354865). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1098907). This sequence change affects an acceptor splice site in intron 4 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened 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 ovarian cancer (PMID: 29522266, 32107557).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298949 SCV002598984 likely pathogenic Hereditary breast ovarian cancer syndrome 2022-09-02 criteria provided, single submitter clinical testing Variant summary: RAD51C c.706-1G>A 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: Four predict the variant abolishes a canonical 3' acceptor site and creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251368 control chromosomes. c.706-1G>A has been reported in the literature in individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome and colorectal cancer (Henn_2019, Yang_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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