Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001212223 | SCV001383800 | likely pathogenic | Fanconi anemia complementation group O | 2019-06-18 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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, 29409816, 22451500, 27622768). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 27622768). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with ovarian cancer (PMID: 27622768). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 135 of the RAD51C protein (p.Cys135Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant also falls at the last nucleotide of exon 2 of the RAD51C coding sequence, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002322030 | SCV002630153 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-02-24 | criteria provided, single submitter | clinical testing | The c.404G>T pathogenic mutation, located in coding exon 2 of the RAD51C gene, results from a G to T substitution at nucleotide position 404. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This alteration was identified in 1/610 German breast only or breast and ovarian families. The index case in this family had ovarian cancer at 70, and a sister with ovarian cancer at 57 who was not tested for the alteration. RT-PCR analysis followed by Sanger sequencing confirmed that this alteration disrupts normal splicing at the donor site of exon 2 leading to missense substitution followed by immediately by a stop codon (p.Cys135Leufs*2) (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169). Two additional alterations have been identified in breast and ovarian families at this position, one of which was also confirmed to disrupt mRNA splicing leading to a truncated protein (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169; Osorio A et al. Hum. Mol. Genet. 2012 Jul;21:2889-98). In addition to the data presented in the literature, this alteration is 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 a disease-causing mutation. |
| Myriad Genetics, |
RCV004033846 | SCV004931386 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 3 | 2024-01-02 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 27622768]. |