Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000561214 | SCV000665893 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-24 | criteria provided, single submitter | clinical testing | The c.80G>T variant (also known as p.C27F), located in coding exon 1 of the BRCA1 gene, results from a G to T substitution at nucleotide position 80. The amino acid change results in cysteine to phenylalanine at codon 27, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, this alteration is predicted to be deleterious by in silico protein analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000696469 | SCV000825032 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2019-03-06 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with phenylalanine at codon 27 of the BRCA1 protein (p.Cys27Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant also falls at the last nucleotide of exon 2 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481469). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant affects the highly conserved Cys27 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 11526114, 22843421). This variant has been reported to affect BRCA1 protein function (PMID: 30209399). 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, |
RCV001077723 | SCV001243695 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |