Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001222374 | SCV001394471 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-04-20 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 950626). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 31907386). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1430 of the BRCA1 protein (p.Pro1430Leu). |
| Ambry Genetics | RCV002327526 | SCV002629600 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-22 | criteria provided, single submitter | clinical testing | The p.P1430L variant (also known as c.4289C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4289. The proline at codon 1430 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235501 | SCV003933889 | uncertain significance | not specified | 2023-05-30 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.4289C>T (p.Pro1430Leu) results in a non-conservative amino acid change in 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 251434 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4289C>T has been reported in the literature in individuals with a personal or family history of breast- and/or ovarian cancer, however without strong evidence for causality (e.g., Kim_2020, Park_2021, Pereira_2022). In addition, the variant was also identified in several healthy controls in a case-control study involving male and female breast cancer patients (e.g., Momozawa_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31907386, 30287823, 34063308, 35980532). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |