Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235734 | SCV000293903 | uncertain significance | not provided | 2016-02-03 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.4055A>T at the cDNA level, p.Glu1352Val (E1352V) at the protein level, and results in the change of a Glutamic Acid to a Valine (GAA>GTA). Using alternate nomenclature, this variant would be defined as BRCA1 4174A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1352Val 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 Glutamic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1352Val occurs at a position that is not conserved and is located in the SCD domain as well as a region known to interact with multiple proteins (Narod 2004, Paul 2014). 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 BRCA1 Glu1352Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV000637763 | SCV000759240 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1352 of the BRCA1 protein (p.Glu1352Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 246375). 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 BRCA1 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Ce |
RCV000235734 | SCV001151327 | uncertain significance | not provided | 2019-05-01 | criteria provided, single submitter | clinical testing | |
| University of Washington Department of Laboratory Medicine, |
RCV003157493 | SCV003851481 | 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). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987475 | SCV004803503 | uncertain significance | not specified | 2024-01-17 | criteria provided, single submitter | clinical testing |