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

dbSNP: rs1057517641

Total submissions: 5

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410256	SCV002144738	pathogenic	Fanconi anemia complementation group O	2022-06-15	criteria provided, single submitter	clinical testing	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. 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).
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.