ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5212G>A (p.Gly1738Arg) (rs80356937)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
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) RCV000112566 SCV000244392 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 RCV000239131 SCV000076876 pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1738 of the BRCA1 protein (p.Gly1738Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (rs80356937, ExAC no frequency). This variant has been reported to segregate with breast and/or ovarian cancer in several families and is a founder mutation in the Greek population (PMID: 17902052, 23536787, 15353005, 24010542, 17453335, 16489001). ClinVar contains an entry for this variant (Variation ID: 55461). Experimental studies have shown that this missense variant is deleterious, as demonstrated by in vitro studies showing reduced transactivation activity as well as compromised nuclear foci formation and centrosome amplification (PMID: 17305420, 18036263, 20516115, 17308087). A different missense substitution at this codon (p.Gly1738Glu) has been determined to be pathogenic (PMID: 18465347, 23113073, 21918854, 11157798, 10811118). This suggests that the glycine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneKor MSA RCV000239131 SCV000296779 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation is a missense mutation, substituting Glycine with Arginine at codon 1738 of the BRCA1 protein p.(Gly1738Arg). The glycine residue is highly conserved among species and is located in a domain of the protein that is not known to be functionally important. There is a large physicochemical difference between glycine and arginine (Grantham Score 125). This variant is not present in population databases (rs80356937) and has been reported in international literature in breast and/or ovarian cancer patients and is a founder mutation in the Greek population (PMID: 17902052, PMID: 23536787, PMID: 15353005, PMID: 24010542, PMID: 17453335, PMID: 16489001). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging. In addition, experimental studies have shown that this missense variant is deleterious (PMID: 17305420, 18036263, 20516115, 17308087). A different missense substitution at this codon (p.Gly1738Glu) has been determined to be pathogenic (PMID: 18465347, PMID: 23113073, PMID: 21918854, PMID: 11157798, PMID: 10811118). This suggests that the glycine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112566 SCV000326218 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000112566 SCV000564322 likely pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000579604 SCV000683272 pathogenic Hereditary cancer-predisposing syndrome 2016-08-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985433 SCV001133617 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282860 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Appears to be associated with disease in multiple families.
Ambry Genetics RCV000579604 SCV001185657 pathogenic Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing The p.G1738R pathogenic mutation (also known as c.5212G>A and 5331G>A), located in coding exon 18 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5212. The glycine at codon 1738 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been classified as pathogenic (p>0.99) 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, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21). This mutation is one of four Greek founder mutations which together account for 73% of mutations identified in BRCA1 in the Greek population (Anagnostopoulos T et al. Breast Cancer Res Treat. 2008;110(2):377-85). In two studies, this variant was identified in 0.4% to 3% of sporadic Greek breast and/or ovarian cancer families and in 3.7% to 12% of Greek carriers of a deleterious BRCA1 or BRCA2 mutation (Armaou S et al. Br J Cancer. 2009,7;101(1):32-7; Stavropoulou AV et al. PLoS One. 2013;8(3)). In addition, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). Multiple functional assays, including protease sensitivity, phosphopeptide binding activity, phosphopeptide binding specificity, and transcriptional assays have shown a deleterious effect (Karchin R et al. PLoS Comput. Biol. 2007;3(2):e26; Lovelock PK et al. Breast Cancer Res. 2007;9(6):R82); Carvalho MA et al.​ Cancer Res. 2007;15;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Thouvenot P et al. PLoS Genet. 2016 Jun 6;12(6):e1006096). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). Based on the available evidence, p.G1738R is classified as a pathogenic mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000239131 SCV001361730 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-18 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5212G>A (p.Gly1738Arg) results in a non-conservative amino acid change located in the BRCT linker domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found not found in 278112 control chromosomes (gnomAD). c.5212G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer where it co-segregated with the disease in over 8 families (e.g. Anagnostopoulos 2008, Konstantopoulou 2008, Chenevix-Trench 2006, Konstantopoulou 2014). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated severely diminished transcriptional activity, destabilization of the BRCT structure, reduced capacity to form foci in response to DNA damage, and increased centrosome amplification (Carvalho 2007, Lovelock 2007, Lee 2010, Thouvenot 2016, Findlay 2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (5x)/likely pathogenic(1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000985433 SCV001447130 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112566 SCV000145396 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000239131 SCV000587480 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000112566 SCV001237926 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.