Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000159848 | SCV000209891 | uncertain significance | not specified | 2017-05-02 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.2935C>A at the cDNA level, p.Arg979Ser (R979S) at the protein level, and results in the change of an Arginine to a Serine (CGT>AGT). Using alternate nomenclature, this variant would be defined as BRCA1 3054C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Arg979Ser 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 Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg979Ser occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Arg979Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000159848 | SCV000600307 | uncertain significance | not specified | 2017-04-01 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001191788 | SCV001359688 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-01 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 979 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV001191788 | SCV002746098 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-22 | criteria provided, single submitter | clinical testing | The p.R979S variant (also known as c.2935C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 2935. The arginine at codon 979 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV002515107 | SCV003335149 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-02-15 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 979 of the BRCA1 protein (p.Arg979Ser). 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: 182078). 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. 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. |
University of Washington Department of Laboratory Medicine, |
RCV001191788 | SCV003849239 | 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). |