Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000656808 | SCV000329144 | uncertain significance | not provided | 2016-08-08 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.8860T>C at the cDNA level, p.Ser2954Pro (S2954P) at the protein level, and results in the change of a Serine to a Proline (TCT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 9088T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser2954Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2954Pro occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser2954Pro is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| ARUP Laboratories, |
RCV000308900 | SCV000602778 | uncertain significance | not specified | 2016-09-12 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000562009 | SCV000661231 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-03 | criteria provided, single submitter | clinical testing | The p.S2954P variant (also known as c.8860T>C), located in coding exon 21 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8860. The serine at codon 2954 is replaced by proline, an amino acid with similar properties. This amino acid position is well 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. |
| Color Diagnostics, |
RCV000562009 | SCV000909499 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-05-05 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001217254 | SCV001389088 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-01 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2954 of the BRCA2 protein (p.Ser2954Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 279707). 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 not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. |