Submissions for variant NM_058216.3(RAD51C):c.145+1G>A

dbSNP: rs757128712

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563566	SCV000671896	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	The c.145+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the RAD51C gene. A similar alteration at this position, 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. 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	RCV000563566	SCV001358236	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-16	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +1 position of intron 1 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251282 chromosomes 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.
Baylor Genetics	RCV003459370	SCV004208052	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2021-10-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003617833	SCV004383560	pathogenic	Fanconi anemia complementation group O	2023-07-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 484741). 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; Invitae). Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 20400964). This variant is present in population databases (rs757128712, gnomAD 0.006%). 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.
Myriad Genetics, Inc.	RCV003459370	SCV004933264	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-02	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.