Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002339493 | SCV002635559 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-01-02 | criteria provided, single submitter | clinical testing | The p.D159N variant (also known as c.475G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 475. The aspartic acid at codon 159 is replaced by asparagine, an amino acid with highly similar properties. In a study of 1100 German high-risk breast and/or ovarian cancer families, this alteration was detected in 1 individual (Meindl A et al. Nat. Genet., 2010 May;42:410-4). Multiple functional studies have demonstrated that this alteration moderately impairs protein function (Meindl A et al. Nat. Genet., 2010 May;42:410-4; Somyajit K et al. J. Biol. Chem., 2012 Jan;287:3366-80; Somyajit K et al. Carcinogenesis, 2015 Jan;36:13-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Leiden Open Variation Database | RCV001195018 | SCV001365261 | likely benign | not specified | 2014-11-02 | no assertion criteria provided | curation | Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. |
| Department of Pathology and Laboratory Medicine, |
RCV001355299 | SCV001550146 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The RAD51C p.Asp159Asn variant was identified in 1 of 2200 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer and was not identified in 960 chromosomes from individuals or families with ovarian cancer or from 5824 control chromosomes from healthy individuals (Meindl 2009). The variant was also identified in the LOVD 3.0 database (not classified). The variant was not identified in dbSNP or ClinVar. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). In one study, this variant partially restored mitocyn-C sensitivity of ΔRad51c DT40 cells compared to the wild-type cDNA; it also resulted in normal RAD51 foci formation when the missense protein was expressed in human RAD51C-mutated fibroblast cells; and was considered to be an unclassified variant (Meindl 2009). The p.Asp159 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |