Submissions for variant NM_007294.4(BRCA1):c.5194-12G>A

dbSNP: rs80358079

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566894	SCV004101452	pathogenic	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.5194-12G>A variant is an intronic variant occurring in intron 19 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.96, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant was reported to result in aberrant mRNA splicing by partial retention of intron 19 (PMIDs: 21673748, 21394826). Another study reported the same aberration as well as exon 20 skipping, however it also reported a higher proportion of full length transcript (PMID: 31843900) (PVS1 (RNA) not applied due to conflicting evidence). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1126348153 (based on Cosegregation LR=6.5; Pathology LR=12.7; Co-occurrence LR=1.3; Family History LR=10799731), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PP4_Very strong).
Invitae	RCV000048851	SCV000076864	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 18 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 17924331, 23278966, 25682074). ClinVar contains an entry for this variant (Variation ID: 55451). 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: 17924331). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21394826, 21673748; Invitae). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077608	SCV000326205	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000583637	SCV000688548	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -12 position of intron 18 of the BRCA1 gene. RNA studies have shown that this variant causes out-of-frame splicing, resulting in expected premature truncation (PMID: 21394826, 21673748, 23278966, 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least 3 individuals affected with breast cancer (PMID: 23278966, 25682074; Color internal data) and also reported to have segregation and family history likelihood ratios for pathogenicity of 532.1 and 363.1, respectively (PMID: 21394826). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048851	SCV000699219	pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5194-12G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 2/5 splice prediction tools predict that this variant creates a novel 3' splicing acceptor site. This prediction was confirmed by two independent studies by sequencing cDNA from the patients carrying the variant of interest (Whiley_2011, Wong-Brown_2013). The studies showed that the altered splicing led to the inclusion of 10bp intronic sequence generating a downstream frameshift mutation (p.His1732Phefs). This variant has been reported in multiple patients with breast cancer and family history of HBOC. This variant is absent in 121410 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including an expert panel. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762996	SCV000893441	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000583637	SCV002643767	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-21	criteria provided, single submitter	clinical testing	The c.5194-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 18 in the BRCA1 gene. This alteration has been classified as as a pathogenic mutation by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton DF et al. Am. J. Hum .Genet. 2007 Nov; 81(5):873-83; Whiley PJ et al. Hum. Mutat. 2011 Jun; 32(6):678-87). Multiple, independent RNA based assays indicate that this variant creates a cryptic splice acceptor site that leads to the insertion of 10 nucleotides and, consequently, a predicted protein frameshift (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun; 32(6):678-87; Théry JC et al. Eur. J. Hum. Genet. 2011 Oct; 19(10):1052-8; Wong-Brown MW et al. Clin. Genet. 2013 Nov; 84(5):505-6). This nucleotide position is highly conserved in available vertebrate species. Of note, this alteration is also designated as IVS19-12G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Sharing Clinical Reports Project (SCRP)	RCV000077608	SCV000109411	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-02-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077608	SCV000145385	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV001171437	SCV001251348	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV000048851	SCV004228863	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 02-11-2014 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.