Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000774667 | SCV000908546 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-10 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with alanine at codon 1714 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant has intermediate impact on BRCA1 function in a haploid cell proliferation assay (PMID: 30219179). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006163). Different variants affecting the same position, p.Val1714Gly and p.Val1714Phe, are considered to be disease-causing (ClinVar variation ID: 55413, 631061), suggesting that valine or similar amino acid at this position is important for protein structure and function. 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 | RCV000774667 | SCV001185512 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-17 | criteria provided, single submitter | clinical testing | The p.V1714A variant (also known as c.5141T>C), located in coding exon 16 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5141. The valine at codon 1714 is replaced by alanine, an amino acid with similar properties. One functional study found that this nucleotide substitution has intermediate function in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001061740 | SCV001226494 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2025-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1714 of the BRCA1 protein (p.Val1714Ala). This variant is not present in population databases (gnomAD no frequency). 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: 629871). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. This variant disrupts the p.Val1714 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20516115, 26344711, 28781887, 29752822, 30209399; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Brotman Baty Institute, |
RCV001072337 | SCV001237698 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |