Submissions for variant NM_058216.3(RAD51C):c.837+1G>A

gnomAD frequency: 0.00002  dbSNP: rs760235677

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221081	SCV000273205	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	clinical testing	The c.837+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the RAD51C gene. This mutation has been associated with loss of heterozygosity in multiple tumors and aberrant splicing based on cDNA studies (Pelttari LM, Hum. Mol. Genet. 2011 Aug; 20(16):3278-88) and is recurrent in Finnish breast/ovarian cancer families, with haplotype analysis supporting a founder effect in this population (Nurmi A et al. Int J Cancer, 2019 11;145:2692-2700; Pelttari LM et al. Clin Genet, 2018 03;93:595-602). This nucleotide position is highly conserved in available vertebrate species. 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). 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 pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986012	SCV001134790	pathogenic	not provided	2019-05-30	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225213	SCV001397454	pathogenic	Fanconi anemia complementation group O	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs760235677, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21616938, 25470109, 28802053, 30927251). ClinVar contains an entry for this variant (Variation ID: 229854). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 21616938). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000024267	SCV004931894	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-03	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.
OMIM	RCV000024267	SCV000045558	risk factor	Breast-ovarian cancer, familial, susceptibility to, 3	2011-08-15	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV001195027	SCV001365279	pathogenic	Ovarian neoplasm	2014-11-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.