Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000212183 | SCV000210178 | uncertain significance | not provided | 2014-05-29 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.4504C>T at the cDNA level, p.Pro1502Ser (P1502S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant was predicted to create additional kinase binding sites, the clinical significance of which is unclear (Tram 2013). BRCA1 Pro1502Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1502Ser occurs at a position that is highly variable across species and is located in the SQ/TQ cluster domain (Roy 2012). In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. The variant is listed once in the Breast Information Core (BIC) database as having unknown significance. Based on currently available information, it is unclear whether BRCA1 Pro1502Ser is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000214845 | SCV000274417 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-29 | criteria provided, single submitter | clinical testing | The p.P1502S variant (also known as c.4504C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4504. The proline at codon 1502 is replaced by serine, an amino acid with similar properties. Using an in vivo prediction tool, this variant was predicted to create an additional kinase binding site (Tram E et al. PLoS ONE 2013; 8(5):e62468). 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. |
| Color Diagnostics, |
RCV000214845 | SCV000909022 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-01-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001322721 | SCV001513608 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2021-02-21 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55218). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 1502 of the BRCA1 protein (p.Pro1502Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. |
| Breast Cancer Information Core |
RCV000112350 | SCV000145110 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2003-12-23 | no assertion criteria provided | clinical testing |