Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000637525 | SCV000758987 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-08-04 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 531302). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.134+3A nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12402332, 12759930). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (PMID: 32123317; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001284530 | SCV001470368 | likely pathogenic | not provided | 2024-05-08 | criteria provided, single submitter | clinical testing | The BRCA1 c.134+3A>T variant has been reported in an RNA study to cause skipping of exon 3 and the creation of a premature termination codon in the affected transcript (PMID: 32123317 (2020)). A saturation genome editing assay measuring DNA repair-dependent cell survival classified this variant as non-functional (PMID: 30209399 (2018)). To the best of our knowledge, this variant has not been reported in individuals with BRCA1-related conditions in the published literature. However, a different variant at the same nucleotide, BRCA1 c.134+3A>C (also known as IVS3+3A>C), has been observed in a hereditary breast/ovarian cancer family and shown to cause aberrant splicing as well (PMID: 12759930 (2003)). The BRCA1 c.134+3A>T variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. |
| Ambry Genetics | RCV002386027 | SCV002691898 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-23 | criteria provided, single submitter | clinical testing | The c.134+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 2 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration results in skipping of coding exon 2 (also known as exon 3 in the literature) resulting in a transcript with a premature termination codon (Wai HA et al. Genet Med, 2020 06;22:1005-1014). 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). In addition, several variants at the same donor site, including BRCA1 c.134+5G>A and BRCA1 c.134+5G>T, cause the same splice defect (Ambry internal data; Baert A et al. Hum. Mutat., 2018 04;39:515-526). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Baylor Genetics | RCV001076221 | SCV004216931 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2022-08-03 | criteria provided, single submitter | clinical testing | |
| Brotman Baty Institute, |
RCV001076221 | SCV001241935 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |