Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000226938 | SCV000289824 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2022-06-03 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Gly1748 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16644204, 24845084, 28781887, 30209399, 31131967). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399, 30765603). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 240819). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29161300). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1748 of the BRCA1 protein (p.Gly1748Arg). |
| Mendelics | RCV000989869 | SCV001140478 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001023794 | SCV001185714 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-28 | criteria provided, single submitter | clinical testing | The p.G1748R variant (also known as c.5242G>C), located in coding exon 18 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5242. The glycine at codon 1748 is replaced by arginine, an amino acid with 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 10;562:217-222). A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992). This alteration has been detected in a cohort of 418 Brazilian hereditary breast and ovarian cancer probands (Alemar B et al. PLoS ONE, 2017 Nov;12:e0187630). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Brotman Baty Institute, |
RCV000989869 | SCV001242460 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |