Submissions for variant NM_007294.4(BRCA1):c.81-9C>G

dbSNP: rs80358127

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111718	SCV001161638	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.996447
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049152	SCV000077165	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in aberrant mRNA splicing and introduces a premature termination codon (PMID: 20614180, 23893897, 30209399). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 30415210). ClinVar contains an entry for this variant (Variation ID: 55719). This variant is also known as IVS2-9C>G. This variant has been observed in individual(s) with breast cancer (PMID: 18704682). This variant is present in population databases (rs80358127, gnomAD 0.006%). This sequence change falls in intron 2 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.
Ambry Genetics	RCV001027266	SCV001189799	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-19	criteria provided, single submitter	clinical testing	The c.81-9C>G intronic pathogenic mutation results from a C to G substitution 9 nucleotides upstream from coding exon 2 in the BRCA1 gene. This nucleotide position is poorly conserved in available vertebrate species, however, thymidine is the only other observed alternate nucleotide. Using the BDGP and ESEfinder splice site prediction tools predicts a weakening in the native splice acceptor site efficiency and the creation of a new alternate splice acceptor site 8 nucleotides upstream from the native. RNA studies have confirmed this cryptic splice site is used resulting in abnormal splicing in the set of samples tested (Ambry internal data; Joosse SA et al. Breast Cancer Res. Treat., 2012 Apr;132:379-89). In addition, this alteration was shown to be functionally deleterious in a high-throughput haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the majority of evidence available to date, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000111718	SCV004216886	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-11-10	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111718	SCV000144229	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111718	SCV001242306	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529263	SCV001742414	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001529263	SCV001905849	pathogenic	not provided		no assertion criteria provided	clinical testing