ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.547+1G>A (rs80358030)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000112729 SCV000488302 likely pathogenic Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Invitae RCV000533400 SCV000636043 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) who underwent genetic testing for hereditary breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 125881). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). 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.
Ambry Genetics RCV000570102 SCV000668385 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.547+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of 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 donor site; however, direct evidence is unavailable. Close match alterations at the same canonical donor site, BRCA2 c.547+2T>A and BRCA2 c.547+1G>T, cause skipping of coding exon 6 (designated as exon 8 in the literature) which will produce an out-of-frame transcript with a predicted premature stop codon (Ambry internal data; Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Colombo M et al. PLoS ONE 2013 Feb;8:e57173). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000533400 SCV000699262 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-06-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.547+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant was absent in 251436 control chromosomes. c.547+1G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Mucaki_2011, Ryu_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). One submitter cites internal data corroborating an impact of splicing. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Research and Development, ARUP Laboratories RCV001657697 SCV001877368 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2021-05-21 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112729 SCV000145612 pathogenic Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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