ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5363G>T (p.Gly1788Val) (rs80357069)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031241 SCV000244400 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
Invitae RCV000048961 SCV000076974 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1788 of the BRCA1 protein (p.Gly1788Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs80357069, ExAC 0.001%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 9796975, 21614564, 18512148, 16267036, 26689913). This variant is also known as 5482G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37660). Based on multiple multifactorial likelihood algorithms using genetic and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134, 17924331, 18418466, 27272900). Experimental studies have shown that this missense change affects BRCA1 protein structural stability, peptide binding specificity, and transcriptional activity (PMID: 20516115, 15689452, 14534301, 26689913). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162885 SCV000213372 pathogenic Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
GeneDx RCV000235698 SCV000292527 pathogenic not provided 2016-09-27 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5363G>T at the cDNA level, p.Gly1788Val (G1788V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant has been previously published as BRCA1 5482G>T. This variant was observed in individuals with a personal and/or family history of breast or ovarian cancer (Berchuck 1998, Chen 2009, Cao 2013, Kanchi 2014, Lu 2015). Functional studies show that this residue is essential for protein stability and folding and BRCA1 Gly1788Val results in sensitivity to proteolytic degradation, decreased transcriptional activation and decreased homology directed repair (Williams 2003, Gaiser 2004, Williams 2004, Phelan 2005, Glover 2006, Lee 2010, Rowling 2010, Lu 2015). In addition, this variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence data. BRCA1 Gly1788Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly1788Val occurs at a position that is conserved through species and is located in the BRCT domain and in a region known to interact with multiple proteins (UniProt, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031241 SCV000296368 pathogenic Breast-ovarian cancer, familial 1 2015-10-28 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031241 SCV000326293 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048961 SCV000699249 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5363G>T (p.Gly1788Val) variant causes a missense change involving a conserved nucleotide located within the C-terminal BRCT domain with 4/5 in silico tools predicting a damaging outcome, which is further supported by multiple functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121230, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Counsyl RCV000031241 SCV000785680 pathogenic Breast-ovarian cancer, familial 1 2017-11-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235698 SCV000887726 pathogenic not provided 2015-10-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002191 SCV001160062 pathogenic not specified 2018-10-26 criteria provided, single submitter clinical testing The BRCA1 c.5363G>T; p.Gly1788Val variant (rs80357069) is reported in the literature in multiple individuals affected with breast or ovarian cancer (Berchuck 1998, Chen 2009, Easton 2007, Kwong 2015, Lu 2015, Sun 2017, Zhang 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37660), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1788 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show protease sensitivity, impaired protein folding, and reduced stability, homologous recombination activity, and transcriptional activity (Lee 2010, Lu 2015, Phelan 2005, Williams 2003). Based on available information, the p.Gly1788Val variant is considered to be pathogenic. References: Berchuck A et al. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res. 1998 Oct;4(10):2433-7. Chen W et al. BRCA1 germline mutations and tumor characteristics in Chinese women with familial or early-onset breast cancer. Breast Cancer Res Treat. 2009 Sep;117(1):55-60. Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Phelan CM et al. Classification of BRCA1 missense variants of unknown clinical significance. J Med Genet. 2005 Feb;42(2):138-46. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Williams RS et al. Detection of protein folding defects caused by BRCA1-BRCT truncation and missense mutations. J Biol Chem. 2003 Dec 26;278(52):53007-16. Zhang J et al. Prevalence and characterization of BRCA1 and BRCA2 germline mutations in Chinese women with familial breast cancer. Breast Cancer Res Treat. 2012 Apr;132(2):421-8.
Sharing Clinical Reports Project (SCRP) RCV000031241 SCV000053845 pathogenic Breast-ovarian cancer, familial 1 2011-09-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031241 SCV000145482 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 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.