ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2967T>A (p.Phe989Leu) (rs876659270)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217575 SCV000275534 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000238878 SCV000489535 uncertain significance Breast-ovarian cancer, familial 1 2016-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000480997 SCV000567394 uncertain significance not provided 2016-03-10 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2967T>A at the cDNA level, p.Phe989Leu (F989L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTA). Using alternate nomenclature, this variant would be defined as BRCA1 3086T>A. This variant was observed in 1/273 individuals with personal and/or family histories suspicious for Hereditary Breast and Ovarian Cancer (Carney 2010). BRCA1 Phe989Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Phe989Leu occurs at a position that is not conserved and is located in the DNA binding domain (Narod 2004) In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Phe989Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000217575 SCV000904783 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
Invitae RCV000813770 SCV000954142 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 989 of the BRCA1 protein (p.Phe989Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 21218378) and endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 231629). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is 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.
Sharing Clinical Reports Project (SCRP) RCV000238878 SCV000297593 uncertain significance Breast-ovarian cancer, familial 1 2014-02-07 no assertion criteria provided clinical testing

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.