Submissions for variant NM_058216.3(RAD51C):c.1027-3C>G

dbSNP: rs587782459

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131545	SCV000186544	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	The c.1027-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 9 in the RAD51C gene. This nucleotide position is highly conserved in available vertebrate species. In a cohort of 124 patient with pancreatic cancer and another Hereditary Breast and/or Ovarian- or Lynch syndrome-related cancer, this variant was reported in a female patient with a personal history of ovarian, breast, and pancreatic cancer and a positive family history of cancer (Dudley B et al. Cancer. 2018 Apr;124:1691-1700). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204070	SCV000260236	uncertain significance	Fanconi anemia complementation group O	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ovarian cancer (PMID: 5806449). ClinVar contains an entry for this variant (Variation ID: 142429). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 35806449; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131545	SCV000679743	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131545	SCV001358457	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-05	criteria provided, single submitter	clinical testing	This variant causes a C>G nucleotide substitution at the -3 position of intron 8 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. 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 not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001588988	SCV001814280	uncertain significance	not provided	2020-08-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Observed in individual with a personal history of pancreatic, breast, and ovarian cancer (Dudley 2018); This variant is associated with the following publications: (PMID: 29360161)
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV002265619	SCV002548541	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2022-05-15	criteria provided, single submitter	clinical testing	RAD51C:c.1027-3C>G variant is absent from the large population studies (GnomAd). The variant is predicted to reduce the strenght of natural acceptor splice site by in silico splicing tools. Functional RNA study has shown that the variant causes an inconclusive splicing abberation (PMID: 35806449). Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PM2, PP3, PS3-m).
Baylor Genetics	RCV002265619	SCV004209774	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-16	criteria provided, single submitter	clinical testing