ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.594-2A>C (rs80358033)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031267 SCV000577983 benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation In our experience this variant always co-occurs in cis with c.641A>G. The haplotype of c.[594-2A>C; 641A>G] has been shown to be not pathogenic from comprehensive clinical studies (PMID:27008870). We recommend that if c.594-2A>C is detected in an individual, presence of c.641A>G should be verified. If co-occurrence is confirmed, the combination of the two variants is classified as not pathogenic/benign (see SCV000282252.1). If c.594-2A>G is detected alone, assume clinical significance uncertain in the absence of further evidence.
Invitae RCV000049067 SCV000077080 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the BRCA1 gene. It is expected to disrupt RNA splicing. This variant is present in population databases (rs80358033, ExAC 0.003%). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 12601471, 16211554, 16683254, 25366421, 25639900, 10923033), an individual affected with uterine and esophageal cancer (PMID: 22811390), and an individual affected with pancreatic cancer (PMID: 28767289). This variant is also known as IVS9-2A>C and 713-2A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37686). This variant has been reported in trans with a pathogenic BRCA1 variant, exon13ins6kb, suggesting that the c.594-2A>C is not a primary cause of disease (PMID: 25639900). This variant has been reported to be in cis with c.641A>G in several cases (PMID: 27008870, 29254167). Experimental studies have shown that this change results in the generation of two aberrant transcripts, one that leads to out-of-frame skipping of exon 9 (denoted as del10), and one that leads to the in-frame activation of a cryptic acceptor splice site located 21 nucleotides upstream of the natural splice site in intron 8 (i21d) (PMID: 23239986, 24212087, 24667779). However, an in-frame BRCA1 isoform that skips exons 8 and 9 (also known as exons 9 and 10) is expressed in normal blood and breast tissue, suggesting that this isoform may not be deleterious (PMID: 24569164). Additionally, two other BRCA1 isoforms, one that skips exon 14 and another one that retains intron 20 (also known as exon 15 and intron 21), have been shown to be expressed by cell lines carrying c.[594-2A>C;641A>G]. Neither of these isoforms are thought to be associated with increased risk of disease (PMID: 29774201). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131863 SCV000186918 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing Insufficient evidence
CSER _CC_NCGL, University of Washington RCV000049067 SCV000190088 likely benign Hereditary breast and ovarian cancer syndrome 2016-05-18 criteria provided, single submitter research
GeneDx RCV000159940 SCV000210077 likely benign not specified 2018-01-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768650 SCV000219194 uncertain significance Breast and/or ovarian cancer 2017-07-26 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000049067 SCV000266035 likely benign Hereditary breast and ovarian cancer syndrome 2017-07-11 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000159940 SCV000586870 uncertain significance not specified 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000159940 SCV000591290 uncertain significance not specified 2016-08-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588403 SCV000699277 uncertain significance not provided 2016-04-07 criteria provided, single submitter clinical testing Variant Summary: c.594-2A>C is located at a conserved position, predicted by Mutation Taster to be disease causing. 5/5 alamut algorithms predict this variant to impact splicing, and ESE finder predicts the addition of a SRp40 binding motif. This variant always co-occurs in cis with c.641A>G. In experiments where only c.594-2A>C was tested, results has shown that individual c.594-2A>C has similar splicing pattern with slightly increased fraction of naturally occurring ex10del (de la Hoya, 2016) exon 10 splicing regulatory element(s). This variant has been found in multiple HBOC patients in the absence of known pathogenic variants. In addition, it has co-occurred with (unspecified) deleterious mutation in BRCA2 in several families (Myriad data) and 2 different pathogenic variants in BRCA1 in another 2 families. The combined odds for causality for c.[594-2A>C; 641A>G] considering case-control, segregation, and breast tumor pathology information was 3.23xe-8. In addition, most of the reputable databases/diagnostic centers classify variant as VUS. Based on the latest data c.[594-2A>C; 641A>G] carriers (but not necessarily carriers of a potential BRCA1 allele in which c.594-2A>C is not linked to c.641A>G) should not be considered at high-risk of developing BRCA1-associated cancers. Taking all evidence together, the variant was classified as a VUS.
Color RCV000131863 SCV000910719 likely benign Hereditary cancer-predisposing syndrome 2016-07-27 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031267 SCV000053872 not provided Breast-ovarian cancer, familial 1 2010-03-15 no assertion provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031267 SCV000145639 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000031267 SCV000187727 pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided literature only
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000159940 SCV000587066 uncertain significance not specified 2014-01-31 no assertion criteria provided research
King Laboratory,University of Washington RCV001171441 SCV001251352 pathogenic Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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