Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000573696 | SCV000661322 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-06-30 | criteria provided, single submitter | clinical testing | The p.E2260K variant (also known as c.6778G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6778. The glutamic acid at codon 2260 is replaced by lysine, an amino acid with similar properties. In one study, this alteration was reported as a variant of uncertain significance in 1 of 434 Nigerian breast cancer patients (Fackenthal JD et al. Int. J. Cancer 2012 Sep; 131(5):1114-23). 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. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001248161 | SCV001421630 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-10-17 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with breast cancer (PMID: 22034289). ClinVar contains an entry for this variant (Variation ID: 479334). This sequence change replaces glutamic acid with lysine at codon 2260 of the BRCA2 protein (p.Glu2260Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. |
| University of Washington Department of Laboratory Medicine, |
RCV000573696 | SCV003847447 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
| All of Us Research Program, |
RCV004802192 | SCV005424552 | uncertain significance | BRCA2-related cancer predisposition | 2024-03-05 | criteria provided, single submitter | clinical testing |