Submissions for variant NM_058216.3(RAD51C):c.404G>C (p.Cys135Ser)

dbSNP: rs767796996

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478459	SCV000565458	likely pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal and family history of breast or ovarian cancer (PMID: 27622768); Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing (PMID: 33333735, 27622768); This variant is associated with the following publications: (PMID: 27622768, 31782267, 33333735, 14704354, 31341520, 34923718)
Ambry Genetics	RCV000566450	SCV000671879	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The c.404G>C pathogenic mutation (also known as p.C135S), located in coding exon 2 of the RAD51C gene, results from a G to C substitution at nucleotide position 404. The amino acid change results in cysteine to serine at codon 135, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses have shown that this alteration leads to the insertion of 27 nucleotides of intronic sequence between exons 2 and 3 and introduces a premature stop codon (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169, Ambry internal data). This alteration has been identified in two female probands with breast cancer and family histories of breast or breast and ovarian cancer (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000576215	SCV000676959	pathogenic	Fanconi anemia complementation group O	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 135 of the RAD51C protein (p.Cys135Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 27622768; Invitae). ClinVar contains an entry for this variant (Variation ID: 418441). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 27622768; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.404G nucleotide in the RAD51C gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22451500, 27622768, 29409816; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000566450	SCV000691235	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the last nucleotide of exon 2 of the RAD51C gene and replaces cysteine with serine at codon 135 of the RAD51C protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study using carrier-derived RNA has shown that the variant leads to the use of an alternative splice donor site, resulting in the inclusion of the first 27 nucleotides of intron 2 in the RNA transcript (PMID: 27622768). The aberrant transcript is predicted to create a premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 27622768). This variant has not been identified 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.
Revvity Omics, Revvity	RCV000576215	SCV002019012	likely pathogenic	Fanconi anemia complementation group O	2019-12-23	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003334388	SCV004042797	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-08-17	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1_STR, PM5, PS3_SUP, PS4_SUP, PM2_SUP, PP3
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478459	SCV004220141	likely pathogenic	not provided	2023-04-20	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 27622768 (2017)). In a large-scale breast cancer association study, the variant was seen in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). Published functional studies show that this variant creates an aberrant isoform resulting in reduced expression levels of the RAD51C protein in affected individuals (PMID: 27622768 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.