ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5117G>A (p.Gly1706Glu) (rs80356860)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
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) 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
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.
Ambry Genetics RCV000221607 SCV000277516 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing The p.G1706E variant (also known as c.5117G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5117. The glycine at codon 1706 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in numerous breast and ovarian cancer families and has been described as a Spanish founder mutation that segregates with disease in multiple, affected family members (Osorio A et al. Br J Cancer. 2000 Apr;82(7):1266-70; Diez O et al. Hum Mutat. 2003 Oct;22(4):301-12; Janavicius R. EPMA J. 2010 Sep;1(3):397-412; Iyevleva AG et al. Cancer Lett. 2010 Dec 8;298(2):258-63). Functional assays have also shown this alteration to have a deleterious biological effect (Carvalho MA et al. Cancer Res. 2007 Feb 15;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Woods NT et al. npg Genomic Medicine 2016: 1:16001). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Iversen ES Jr et al. Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1078-88; Lindor NM et al. Hum Mutat. 2012 Jan;33(1):8-21). Further, internal structural analysis suggests this alteration is likely pathogenic due to a highly increased global energy change as well as a higher local energy increase compared to other pathogenic variants within close proximity (Ambry Internal Data; Birrane G et al. Biochemistry, 2007 Jul;46:7706-12; Williams RS et al. Cell, 2009 Oct;139:87-99). Of note, this alteration is also referred to as 5236G>A in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000256122 SCV000321440 pathogenic not provided 2020-11-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: decreased transcription activation, abnormal protease sensitivity, binding specificity, and phosphopeptide binding, sensitivity to cisplatin, and absent ability to support growth in BRCA1-deficient mouse embryonic stem cells (Bouwman 2013, Thouvenot 2016, Woods 2016, Fernandes 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in multiple individuals with breast and/or ovarian cancer, and segregated with disease in at least one family (Osorio 2002, Esteban-Cardenosa 2004, Ivevleva 2010); Also known as 5236G>A; This variant is associated with the following publications: (PMID: 17305420, 20727672, 15235020, 15172985, 26071757, 23867111, 30209399, 27272900, 30765603, 17924331, 26780556, 14684619, 17308087, 21447777, 11979449, 12955716, 10755399, 20516115, 21990134, 28781887, 29446198, 32318955, 32123317)
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000219187 SCV000699203 pathogenic Hereditary breast and ovarian cancer syndrome 2021-02-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5117G>A (p.Gly1706Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251342 control chromosomes. c.5117G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of Homology Directed Repair (HDR) activity (example, Findlay_2018). Six clinical diagnostic laboratories, one consortium (CIMBA) and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4) to include the expert panel / likely pathogenic(n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256122 SCV000887714 likely pathogenic not provided 2020-08-10 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color Health, Inc RCV000221607 SCV000908991 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170590 SCV001333178 pathogenic Breast and/or ovarian cancer 2019-04-09 criteria provided, single submitter clinical testing
Institute of Genomics,University of Tartu RCV000031219 SCV001430695 pathogenic Breast-ovarian cancer, familial 1 criteria provided, single submitter research
Invitae RCV000219187 SCV001582576 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 1706 of the BRCA1 protein (p.Gly1706Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 10755399, 11979449, 12385650, 20727672, 29446198). This variant is also known as 5236G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37638). This variant has been reported to affect BRCA1 protein function (PMID: 30209399, 28781887, 23867111, 20516115). This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant (p.Gly1706Arg) that disrupt this residue have been determined to be pathogenic (PMID: 25948282, 22144684, 17262179, 27616075, 30209399, 30458859). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001659883 SCV001878731 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031219 SCV000053819 likely pathogenic Breast-ovarian cancer, familial 1 2011-02-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031219 SCV000145318 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031219 SCV001243570 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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.