Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_StrongPM2_SupportingPP3
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003343/MONDO:0011450/092
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
- -
Likely pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Feb 11, 2014
- -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
- -
Hereditary breast ovarian cancer syndrome Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 17, 2023
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 07, 2017
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. -
not provided, no classification provided
phenotyping only
GenomeConnect - Invitae Patient Insights Network
-
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. -
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 21, 2020
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. -
BRCA1-related cancer predisposition Pathogenic:1
Pathogenic, reviewed by expert panel
curation
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Jun 11, 2024
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). -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 31, 2018
- -
Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1