ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.442-1G>T (rs1351019392)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548280 SCV000635975 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 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). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 462651). 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). Experimental studies have shown that this variant disrupts the consensus splice site and strengthens a cryptic acceptor site in exon 7 (also known as exon 8 in the literature), located 3 nucleotides downstream of the natural splice site. This results in an in-frame deletion of 1 amino acid (p.Gln148del), but otherwise preserves the integrity of the reading frame (PMID: 24569164). These studies suggest that the clinical significance of this splice variant may be uncertain. 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.
Counsyl RCV000663008 SCV000786017 likely pathogenic Breast-ovarian cancer, familial 1 2018-02-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781007 SCV000918755 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.442-1G>T 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. However, computational splicing tools have mixed results, where several predict the 3' acceptor site to be abolished, but also predict the strengthening of a cryptic 3' acceptor site that would result in an in-frame deletion of several amino acids. Due to this ambiguity and data from a publication, Colombo_2014, the ENIGMA Consortium recommends classifying certain splice site variants as Class 3 (VUS) in BRCA1 and BRCA2, including the variant of interest. To our knowledge, no occurrence of c.442-1G>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
Ambry Genetics RCV001022460 SCV001184199 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.