Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000112487 | SCV000326144 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
Department of Medical Genetics, |
RCV000112487 | SCV000564395 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2017-01-20 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000496666 | SCV004848395 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-06-19 | criteria provided, single submitter | clinical testing | The c.5075-2A>C variant in BRCA1 has been identified in 10 individuals with BRCA1-related cancer (Heramb 2018 PUBMED ID: 29339979, Meisel 2017 PUBMED ID: 28324225, Park 2018 PUBMED ID: 29673794, Trujillano 2015 PUBMED: 25556971). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. |
Ambry Genetics | RCV004018959 | SCV005026096 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-10 | criteria provided, single submitter | clinical testing | The c.5075-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 16 in the BRCA1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is insufficient (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). 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 Oct;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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Clinical Genetics Laboratory, |
RCV001353955 | SCV005199704 | pathogenic | not provided | 2022-11-15 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostics Laboratory, |
RCV004018959 | SCV005901942 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-10-08 | criteria provided, single submitter | clinical testing | PVS1, PS3, PM2_Supporting c.5075-2A>C, located in a canonic splicing site of the BRCA1, is predicted to alter splicing, probably causing the skipping of exon 17 (18 according BIC nomenclature) (r.5075_5152del, p.(Asp1692_Trp1718delinsGly)). This alteration is expected to preserve reading frame but the altered region is critical to protein function (PVS1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). BRCA1 c.5075-2A>C was reported by one calibrated study incorporating mRNA splicing effects to affect protein function similar to pathogenic control variants (PMID: 30209399) (PS3). To our knowledge, no relevant clinical data has been reported for this variant. Based on the currently available information, c.5075-2A>C is classified as a pathogenic variant according to ClinGen-BRCA1Guidelines version v1.0.0. |
Breast Cancer Information Core |
RCV000112487 | SCV000145298 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion criteria provided | clinical testing | ||
Research Molecular Genetics Laboratory, |
RCV000496666 | SCV000587456 | pathogenic | Hereditary breast ovarian cancer syndrome | 2014-01-31 | no assertion criteria provided | research | |
Department of Pathology and Laboratory Medicine, |
RCV001353955 | SCV000591577 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Brotman Baty Institute, |
RCV000112487 | SCV001244045 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro | ||
BRCAlab, |
RCV000112487 | SCV004243951 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2020-03-02 | no assertion criteria provided | clinical testing |