Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001327358 | SCV001518432 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-04-15 | criteria provided, single submitter | clinical testing | 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. Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 7 (PMID: 24569164). ClinVar contains an entry for this variant (Variation ID: 1026850). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29907814). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. |
| Ambry Genetics | RCV002329294 | SCV002629208 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-28 | criteria provided, single submitter | clinical testing | The c.442-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 6 in the BRCA1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of one amino acid; however, the exact functional impact of the deleted amino acid is unknown at this time (Ambry internal data). This single amino acid loss is a naturally occurring isoform and may be referred to as Δ8p in some literature (Colombo M et al. Hum Mol Genet. 2014; 23:3666-80). Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002493710 | SCV002796365 | uncertain significance | Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S | 2022-02-07 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003462902 | SCV004215186 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2024-01-20 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004690079 | SCV005185502 | uncertain significance | not specified | 2024-05-06 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.442-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site. Three predict the variant strengthens a cryptic 3' acceptor site. One predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. A study shows that disruption of this splice site results in activation of a cryptic splice site three bp downstream (PMID 24569164). The variant was absent in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442-2A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29907814, 24569164). ClinVar contains an entry for this variant (Variation ID: 1026850). Based on the evidence outlined above, the variant was classified as uncertain significance. |