ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4485-2A>T

dbSNP: rs80358054
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000500292 SCV000759111 likely pathogenic Hereditary breast ovarian cancer syndrome 2017-11-08 criteria provided, single submitter clinical testing 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. This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 433715). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 13 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353851 SCV000591520 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The c.4485-2A>T variant has not been previously reported in the literature. It is predicted to cause abnormal splicing because the nucleotide substitution occurs in the -2 position of the 5' splice site of the splice consensus sequence. Furthermore, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 5 of 5 different programs increasing the likelihood this variant causes abnormal splicing. In addition, another variant at this same position, different nucleotide change (c.4485-2A>G), has been previously reported in the HGMD and 7x in the BIC database as a clinically significant variant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.

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.