ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2773A>G (p.Ile925Val) (rs4986847)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164476 SCV000215121 likely benign Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing Other data supporting benign classification;In silico models in agreement (benign)
GeneDx RCV000235778 SCV000293090 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2773A>G at the cDNA level, p.Ile925Val (I925V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). Using alternate nomenclature, this variant would be defined as BRCA1 2892A>G. This variant was identified in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA1 Ile925Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Ile925Val is located in the DNA binding domain and RAD51 binding domain (Chen 1998, Paul 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Ile925Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000459020 SCV000549350 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 925 of the BRCA1 protein (p.Ile925Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. 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: 185111). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV000164476 SCV000903495 likely benign Hereditary cancer-predisposing syndrome 2016-11-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192521 SCV001360721 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2773A>G (p.Ile925Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The valine amino acid residue resulting from this variant has been identified in multiple mammalian species, providing supporting evidence that the variant may not adversely affect protein function (Fleming_2003, Ramirez_2004, Lou_2014). The variant allele was found at a frequency of 8e-06 in 251016 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2773A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant was found in one individual in a cohort of healthy women over 70 years of age with no history of cancer (FLOSSIES database). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant with conflicting assessments (2x likely benign, 2x uncertain significance). Based on the evidence outlined above, the variant was classified as uncertain significance-possibly benign.

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.