Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129338 | SCV000184101 | uncertain significance | Hereditary cancer-predisposing syndrome | 2013-11-13 | criteria provided, single submitter | clinical testing | ​The p.D224A variant (also known as c.671A>C or 899A>C) is located in coding exon 7 of the BRCA2 gene. This alteration results from an A to C substitution at nucleotide position 671. The aspartic acid at codon 224 is replaced by alanine, an amino acid with dissimilar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Another amino acid substitution at this position (p.D224V) was described in a family with three cases of female breast cancer and one case of male breast cancer (Evans DG et al. Fam. Cancer 2008;7(2):113-7). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.D224A remains unclear. |
| Labcorp Genetics |
RCV001210283 | SCV001381762 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-09-20 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with alanine at codon 224 of the BRCA2 protein (p.Asp224Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141017). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |