Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000797338 | SCV000936891 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 4 | 2019-11-01 | criteria provided, single submitter | clinical testing | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 C15"). This variant has been observed in several individuals affected with ovarian cancer (PMID: 21822267). ClinVar contains an entry for this variant (Variation ID: 643598). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 115 of the RAD51D protein (p.Gln115His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 4 of the RAD51D coding sequence, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002458440 | SCV002613024 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-26 | criteria provided, single submitter | clinical testing | The p.Q115H variant (also known as c.345G>C), located in coding exon 4 of the RAD51D gene, results from a G to C substitution at nucleotide position 345. The glutamine at codon 115 is replaced by histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in an individual diagnosed with ovarian cancer (Loveday C et al. Nat Genet, 2011 Aug;43:879-882). This nucleotide position is highly conserved in available vertebrate species. This amino acid 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). In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Myriad Genetics, |
RCV000797338 | SCV004932613 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2024-01-04 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21822267]. |
| OMIM | RCV000797338 | SCV000044513 | risk factor | Breast-ovarian cancer, familial, susceptibility to, 4 | 2011-08-07 | no assertion criteria provided | literature only |