ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.145+2T>G

dbSNP: rs1057517641
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410256 SCV000489913 likely pathogenic Fanconi anemia complementation group O 2016-08-04 criteria provided, single submitter clinical testing
Counsyl RCV000411364 SCV000489914 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2016-08-04 criteria provided, single submitter clinical testing
Invitae RCV000410256 SCV002144738 pathogenic Fanconi anemia complementation group O 2022-06-15 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 alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 372087). Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 20400964). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 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.
Ambry Genetics RCV002392935 SCV002698121 likely pathogenic Hereditary cancer-predisposing syndrome 2022-05-27 criteria provided, single submitter clinical testing The c.145+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 1 in the RAD51C gene. Another alteration impacting the same donor site (c.145+1G>T), was identified in 1/480 German families with both breast and ovarian cancer, and was not observed in 620 breast cancer only families or 2912 healthy controls; RT-PCR analysis confirmed that this alteration disrupts splicing and results in an aberrant transcript, and the authors identified loss of the wild-type allele in tumor cells from an individual with this alteration (Meindl A et al. Nat. Genet., 2010 May;42:410-4). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc. RCV000411364 SCV004019290 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2023-02-27 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.

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