ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5117G>A (p.Gly1706Glu) (rs80356860)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221607 SCV000277516 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Good segregation with disease (lod 1.5-3 = 5-9 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000031219 SCV000145318 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000221607 SCV000908991 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031219 SCV000326159 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031219 SCV000244383 pathogenic Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
GeneDx RCV000256122 SCV000321440 pathogenic not provided 2016-05-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5117G>A at the cDNA level, p.Gly1706Glu (G1706E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). Using alternate nomenclature, this pathogenic variant has been previously published as BRCA1 5236G>A and was observed in multiple individuals with breast and/or ovarian cancer, at least three of whom were related (Osorio 2002, Esteban-Cardenosa 2004, Ivevleva 2010). Functional studies assessing transcription activation and binding activity and specificity have supported the pathogenic nature of BRCA1 Gly1706Glu (Carvahlo 2007, Lee 2010, Woods 2016). In addition, Bouwman et al. (2013) suggested that this variant is deleterious based on sensitivity to cisplatin and absent ability to support growth in BRCA1-deficient mouse embryonic stem cells. BRCA1 Gly1706Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly1706Glu occurs at a position that is conserved in mammals and is located in within the BRCT1 domain (Paul 2014). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000219187 SCV000699203 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5117G>A (p.Gly1706Glu) variant located in the BRCT domain causes a missense change involving a conserved nucleotide with 4/5 in silico tools predicting a damaging outcome, which has been confirmed by multiple functional studies. Although, the implications of this variant on transcriptional activity are conflicting, the general consensus across functional studies indicate that p.Gly1706Glu has a deleterious impact on BRCA1 protein function. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals, predominantly of Spanish decent, including co-segregation within multiple families. Furthermore, multiple reputable databases/clinical laboratories cite the variant as "likely pathogenic/pathogenic." Therefore, BRCA1 c.5117G>A has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000219187 SCV000271207 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-11-17 criteria provided, single submitter clinical testing The p.Gly1727Glu variant in BRCA1 has been reported in at least 9 individuals wi th breast cancer, segregated with disease in 2 affected relatives from 1 family (Osorio 2000, Iyevleva 2010, Breast Cancer Information Core (BIC) database), and was absent from large population studies. In vitro functional studies provide s ome evidence that the missense variant may impact protein function (Bouwman 2013 ). However, these types of assays may not accurately represent biological functi on. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, although additio nal studies are required to fully establish its clinical significance, the p.Gly 1727Glu variant is likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256122 SCV000887714 likely pathogenic not provided 2017-11-16 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031219 SCV000053819 likely pathogenic Breast-ovarian cancer, familial 1 2011-02-16 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.