ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.441+1G>A (rs397509172)

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
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258349 SCV000325953 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571202 SCV000673031 likely pathogenic Hereditary cancer-predisposing syndrome 2016-06-06 criteria provided, single submitter clinical testing The c.441+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the BRCA1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort.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. This alteration has been identified in a high-risk breast and ovarian cancer family and associated with aberrant splicing by RT-PCR analysis (Chen X et al, Hum. Mutat. 2006 May; 27(5):427-35).Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294). As such, the c.441+1G>A variant is classified as likely pathogenic.
Color Health, Inc RCV000571202 SCV001345471 pathogenic Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 6 of the BRCA1 gene. RNA studies have reported that this variant causes the out-of-frame deletion of 62 nucleotides from exon 6 that is expected to produce an absent or nonfunctional protein product (PMID: 16619214, 24667779). This variant has been reported in several individuals affected with breast and ovarian cancer (PMID: 16455195, 16619214, 31372034). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV001381878 SCV001580450 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change affects a donor 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 been observed in individual(s) with breast cancer (PMID: 16619214, 29752822). ClinVar contains an entry for this variant (Variation ID: 55195). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16619214). 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). For these reasons, this variant has been 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.