Submissions for variant NM_007294.4(BRCA1):c.5075-2A>C

dbSNP: rs80358066

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112487	SCV000326144	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000112487	SCV000564395	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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, Skane University Hospital Lund	RCV001353955	SCV005199704	pathogenic	not provided	2022-11-15	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	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 (BIC) (BRCA1)	RCV000112487	SCV000145298	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496666	SCV000587456	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353955	SCV000591577	pathogenic	not provided		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112487	SCV001244045	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000112487	SCV004243951	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing