Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483796 | SCV000570240 | uncertain significance | not provided | 2016-05-04 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.9866T>G at the cDNA level, p.Phe3289Cys (F3289C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 10094T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Phe3289Cys 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 Phenylalanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Phe3289Cys occurs at a position that is not conserved and is located in the Cyclin A binding domain (Esashi 2005). 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 Phe3289Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV005090951 | SCV005734503 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-02-15 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 3289 of the BRCA2 protein (p.Phe3289Cys). 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: 421132). 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. |