ClinVar Miner

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

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Total submissions: 17
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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 2020-10-16 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 2020-08-26 criteria provided, single submitter clinical testing The c.594-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 8 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. This alteration is frequently observed as a haplotype BRCA1 c.[594-2A>C; 641A>G] which is classified as benign <span style="font-family:sans-serif,arial,verdana,trebuchet ms">(de la Hoya M <span style="font-family:sans-serif,arial,verdana,trebuchet ms">et al Hum Mol Genet.<span style="font-family:sans-serif,arial,verdana,trebuchet ms"> 2016; Mar). The same study evaluated the splice effect of the haplotype and of each alteration independently in a minigene assay. The independent BRCA1 c.594-2A>G variant produced an in-frame transcript that retains 21 nucleotides of intron 7, r.594-21_594-1ins which was also detected at a low level in the control samples (de la Hoya M et al Hum Mol Genet.<span style="font-family:sans-serif,arial,verdana,trebuchet ms"> 2016; Mar). This isoform is also known as <span style="font-family:dejavusans">&Delta;<span style="font-family:sans-serif,arial,verdana,trebuchet ms">10p in the literature<span style="font-family:sans-serif,arial,verdana,trebuchet ms">. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, as this alteration results in an in-frame insertion that is also present in controls, and since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000131863 SCV000910719 likely benign Hereditary cancer-predisposing syndrome 2016-07-27 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659911 SCV001877372 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354004 SCV000591290 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.594-2A>C variant was identified in the literature in functional, in silico analysis, segregation studies and reviews (Steffensen 2014, Tesoriero 2005, Hoya 2016, Rosenthal 2015). The variant was also identified in dbSNP (ID: rs80358033) as “With Pathogenic, untested allele”; NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles; Exome Aggregation Consortium database (August 8, 2016) in 2 of 109096 chromosomes (freq. 0.00001833) in the following populations: European (Non-Finnish) in 2 of 59486 chromosomes (freq. 0.00003362), but was not seen in African, East Asian, European (Finnish), Latino, South Asian and Other populations. ClinVar and Clinvitae databases (uncertain significance by Invitae, Ambry Genetics, GeneDx, Genetics Diagnostic Laboratory-CHEO; as likely benign by CSER CC NCGI University of Washington; as pathogenic by University of Washington, Dept of Medicine, Pathway Genetics, BIC and Sharing Clinical Report Projects of Myriad did not provide a classification );Fanconi Anemia Mutation Database-LOVD (3X neutral, and LOVD-3.0 9X); ARUP Laboratories BRCA Mutations Database (5- definitely pathogenic.); GeneInsight COGR database (pathogenic by MESHWCRI and NYG, as unknown significance by CHEO and CVHTHP); the BIC database (15X with clinical importance). The c.594-2A>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. A study by Hoya (Hoya 2016) used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A >C. A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594- 2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. Data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of 70–80% truncating transcripts, and 20–30% of in-frame D 9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function. The study confirms that BRCA1 c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20–30% of tumor suppressor function. More generally, the findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes. A review of the variant by Rosenthal (Rosenthal 2015) detailed the following: The expected classification of BRCA1 c.594-2A >C as pathogenic is based on the predicted impact on mRNA splicing at the intron 9/exon 10 boundary. Splicing analysis algorithms predict that this change disrupts normal mRNA splicing because the consensus splice acceptor sequence at this position is highly conserved. Biochemical studies confirm skipping of exon 10 in transcripts from the BRCA1 c.594-2A >C allele, resulting in the loss of 77 nucleotides and premature truncation of the BRCA1 protein (Steffensen 2014 24667779). They re-evaluated BRCA1 c.594-2A >C following published studies of a BRCA1 variant located at a different splice junction, c.591C > T (p.C197C). This variant is predicted to disrupt splicing at the exon 9/intron 9 boundary, but it has long been classified as clinically insignificant based on multiple lines of evidence, including a high frequency in control populations. Given this benign designation, it is somewhat surprising that this variant results in a significant reduction in the production of full length BRCA1 transcripts and the production of abnormal transcripts missing exon 9. However, this is accompanied by an increase in the proportion of an alternatively spliced transcript lacking both exons 9 and 10. In fact, this Δ (9, 10) isoform is normally present at relatively high levels in breast tissue containing only wild-type BRCA1 and may retain at least some BRCA1 function as the deletion of both exons 9 and 10 results in an in-frame deletion of 41 amino acids in a portion of the protein unrelated to homologous repair. These findings raise the possibility that this alternative transcript can ‘rescue’ variants that disrupt splicing for exons 9 and 10, or possibly even sequence changes within those exons. They subsequently performed a systematic review of available data for c.594-2A >C in their clinical database. As of September 23, 2013, they had detected this variant in 110 apparently unrelated individuals as an outcome of comprehensive sequencing and large arrangement analysis. It has been observed in multiple patients from six families who also have deleterious variants in BRCA2, placing this variant in the benign category using the MCO model. BRCA1 c.594-2A >C also falls within the benign range using the HWA. The family testing outcomes do not demonstrate consistent segregation of the variant with breast or ovarian cancer, although they cannot exclude some contribution of the variant to the familial aggregation of cancer. In the past, it has been believed that embryonic lethality was inevitably associated with homozygosity or compound heterozygosity for pathogenic BRCA1 variants, but recent reports of two patients with two deleterious BRCA1 variants in trans has demonstrated that in rare cases this can lead to a clinical condition similar to FA. They have observed a patient with variant c.594-2A>C in trans with the BRCA1 founder variant exon13ins6kb. This patient does not have reported symptoms consistent with FA, which further contradicts a pathogenic interpretation for this variant. Myriad currently reports BRCA1 c.594-2A >C as a ‘special interpretation’ variant based on the as yet unresolved conflict between the predicted impact on protein sequence and function and the available data. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
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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