Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000800802 | SCV000940538 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-09-04 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1734 of the BRCA1 protein (p.Phe1734Cys). 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: 646505). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). 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. |
| Color Diagnostics, |
RCV001524488 | SCV001734355 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-09-28 | criteria provided, single submitter | clinical testing | This missense variant replaces phenylalanine with cysteine at codon 1734 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 shown that the variant protein is non-functional and leads to decreased cell survival in a human haploid cell line-based assay (PMID: 30209399). This variant has not been reported in individuals affected with hereditary cancer in the literature. 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 | RCV001524488 | SCV004058408 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-09 | criteria provided, single submitter | clinical testing | The p.F1734C pathogenic mutation (also known as c.5201T>G), located in coding exon 18 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5201. The phenylalanine at codon 1734 is replaced by cysteine, an amino acid with highly dissimilar properties. One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Two other alterations at the same codon, p.F1734L (c.5202T>G) and p.F1734I (c.5200T>A), have been found to be non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222) and based on internal structural analysis, both alterations decrease the structure stability (Wu Q et al. Mol Cell, 2016 Feb;61:434-448). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Brotman Baty Institute, |
RCV001072514 | SCV001237911 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |