Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000482849 | SCV000567549 | uncertain significance | not provided | 2015-08-04 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.2813C>T at the cDNA level, p.Pro938Leu (P938L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). Using alternate nomenclature, this variant would be defined as BRCA1 2932C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro938Leu 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 Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro938Leu occurs at a position that is not conserved and is located in the DNA binding domain and the region of interaction with BASC and RAD51 (Chen 1998, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Pro938Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV000541701 | SCV000635867 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2017-03-05 | criteria provided, single submitter | clinical testing | In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. This sequence change replaces proline with leucine at codon 938 of the BRCA1 protein (p.Pro938Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. |
Ambry Genetics | RCV001016662 | SCV001177639 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-19 | criteria provided, single submitter | clinical testing | The p.P938L variant (also known as c.2813C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2813. The proline at codon 938 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well 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. |
University of Washington Department of Laboratory Medicine, |
RCV001016662 | SCV003849334 | 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). |