Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219871 | SCV000274493 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-02-05 | criteria provided, single submitter | clinical testing | The p.T2722K pathogenic mutation (also known as c.8165C>A), located in coding exon 17 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8165. The threonine at codon 2722 is replaced by lysine, an amino acid with similar properties. Another disease-causing mutation, p.T2722R, has been described in the same codon (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). This amino acid position is highly conserved in available vertebrate species. This alteration was non-functional in a homology-directed DNA repair (HDR) assay (Ambry internal data). This variant occurs in a structural hotspot region of the protein and is predicted to destabilize the protein and disrupt the native protein-protein (BRCA2-DSS1) interaction (Yang H et al. Science. 2002 Sep;297:1837-48). Based on the majority of available evidence to date, this variant is considered a disease-causing mutation. |
| Labcorp Genetics |
RCV001853527 | SCV002293442 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2021-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with lysine at codon 2722 of the BRCA2 protein (p.Thr2722Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 27878467). ClinVar contains an entry for this variant (Variation ID: 230821). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. This variant disrupts the p.2722 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12145750, 23108138, 18451181, 25146914, 18607349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Myriad Genetics, |
RCV004791339 | SCV005405013 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2024-07-23 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 37713444, 33609447, 37731132, 32444794, 18451181, 18607349, 23108138]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. |