ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.302-3C>G (rs80358051)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219090 SCV000275941 pathogenic Hereditary cancer-predisposing syndrome 2015-05-26 criteria provided, single submitter clinical testing <span style="font-family:arial,sans-serif; font-size:10pt">The<span style="font-family:arial,sans-serif">c.302-3C>Gintronicpathogenic mutation (also known asIVS6-3C>G and421-3C>G) results from a C to G substitution 3 nucleotides upstream from codingexon5 in the<span style="font-family:arial,sans-serif; font-size:10pt">BRCA1<span style="font-family:arial,sans-serif; font-size:10pt">gene. This alteration has been classified as pathogenic (p>0.99) bymultifactorialanalysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity:<span style="font-family:arial,sans-serif">in<span style="font-family:arial,sans-serif; font-size:10pt">silico<span style="font-family:arial,sans-serif; font-size:10pt"><span style="font-family:arial,sans-serif; font-size:10pt">prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883;ValleeM et al. HumMutat. 2012 Jan;33(1):22-8). This alteration has been previously reported and classified as likely pathogenic in theClinVardatabase by the Sharing Clinical Reports Project (SCRP) (available from Accessed 5/22/15). Using theBDGPsplice site prediction tool, this alteration is predicted to abolish the native splice acceptor site, and predicted to create a cryptic acceptor site two nucleotides upstream.Using the ESEfinder splice site prediction tool, this alteration is predicted to weaken the efficiency of the native acceptor splice site,and predicted to create a cryptic acceptor site two nucleotidesupstream.Further, two splicing assays have shown this alteration results in protein truncation (SanzDJ et al,<span style="font-family:arial,sans-serif; font-size:10pt">Clin<span style="font-family:arial,sans-serif; font-size:10pt">. Cancer Res.<span style="font-family:arial,sans-serif; font-size:10pt"><span style="font-family:arial,sans-serif; font-size:10pt">2010 Mar; 16(6):1957-67;MachackovaE et al,<span style="font-family:arial,sans-serif">BMC Cancer2008 ; 8():140). Based on the available evidence,c.302-3C>Gis classified as a pathogenic mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031082 SCV000325537 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV001377525 SCV001574880 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-06 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with personal and/or family history of hereditary breast and/or ovarian cancer (PMID: 22333603, 18489799, 20215541). This variant is also known as IVS6-3C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37501). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18489799, 20215541). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031082 SCV000053678 likely pathogenic Breast-ovarian cancer, familial 1 2008-11-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031082 SCV000144969 pathogenic Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031082 SCV000733675 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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