Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000077566 | SCV000325877 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001377523 | SCV001574878 | pathogenic | Hereditary breast ovarian cancer syndrome | 2024-07-13 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 11 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 19491284, 22333603). This variant is also known as IVS12+1G>T. ClinVar contains an entry for this variant (Variation ID: 55128). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24667779). For these reasons, this variant has been classified as Pathogenic. |
| Genetics and Molecular Pathology, |
RCV002272045 | SCV002556850 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2021-11-22 | criteria provided, single submitter | clinical testing | The BRCA1 c.4185+1G>T variant is classified as Likely Pathogenic (PVS1, PM2) |
| Ambry Genetics | RCV002326771 | SCV002628501 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-03 | criteria provided, single submitter | clinical testing | The c.4185+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 10 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been identified in multiple Korean patients with breast and ovarian cancer (Haffty BG et al. Ann. Oncol., 2009 Oct;20:1653-9; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Ryu JM et al. Breast Cancer Res. Treat., 2019 Jan;173:385-395). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). A close match, last nucleotide, synonymous alteration BRCA1 c.4185G>T induced skipping of coding exon 10 (Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800) and is classified as pathogenic based on a multifactorial analysis model of variant classification (Parsons MT et al. Hum. Mutat., 2019 09;40:1557-1578). In the same study, this variant was classified as likely pathogenic with an elevated family history likelihood ratio (Parsons MT et al. Hum. Mutat., 2019 09;40:1557-1578). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to-date, this alteration is interpreted as a disease-causing mutation. |
| Sharing Clinical Reports Project |
RCV000077566 | SCV000109368 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2012-05-01 | no assertion criteria provided | clinical testing | |
| Breast Cancer Information Core |
RCV000077566 | SCV000145011 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2004-11-25 | no assertion criteria provided | clinical testing |