Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000225876 | SCV000289740 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-04-17 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 91542). 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. 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. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 419 of the BRCA1 protein (p.Val419Gly). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226188 | SCV000698842 | uncertain significance | not specified | 2023-03-16 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.1256T>G (p.Val419Gly) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250804 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1256T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.4876_4877delAA, p.N1626fs*12, internal data), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV001010363 | SCV001170550 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-30 | criteria provided, single submitter | clinical testing | The p.V419G variant (also known as c.1256T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 1256. The valine at codon 419 is replaced by glycine, an amino acid with dissimilar 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, |
RCV001010363 | SCV003846067 | 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). |
| Sharing Clinical Reports Project |
RCV000077059 | SCV000108856 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2013-03-07 | no assertion criteria provided | clinical testing |