ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.211A>G (p.Arg71Gly) (rs80357382)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 25
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) RCV000019263 SCV001161539 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 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 = 0.999388
Invitae RCV000195359 SCV000075726 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 71 of the BRCA1 protein (p.Arg71Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency) . This variant has been reported to segregate with breast and ovarian cancer in many affected families (PMID: 12014998, 20215541), and is defined as a relatively common breast and ovarian cancer causative allele in the Spanish population (PMID: 11385711, 23683081, 27081505). This variant is also known as 330A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 17693). Experimental studies have shown that this substitution does not have a direct impact on protein function (PMID: 11320250, 16403807, 20103620, 21725363, 23161852). However, RT-PCR and mini-gene assays have shown that this substitution destroys the exon 4 natural splice donor site and leads to the usage of a cryptic site located 22 nucleotides upstream (PMID: 11385711, 19123044, 20215541, 21735045). As a result, a premature stop codon, p.Cys64*, is generated. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131899 SCV000186954 pathogenic Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing The p.R71G pathogenic mutation (also known as c.211A>G), located in coding exon 3 of the BRCA1 gene, results from an A to G substitution at nucleotide position 211. Also designated as 330A>G in some published literature, this mutation has been described as a founder mutation originating from the Galicia region of North Western Spain and has been reported in numerous breast and ovarian cancer patients and families (Villarreal-Garza C et al. Breast Cancer Res. Treat. 2015 Apr;150:389-94; Janavièius R. EPMA J. 2010 Sep;1:397-412; Diez O et al. Int. J. Cancer. 1999 Nov;83:465-9; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18(1):112; Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165(3):687-697; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4). Additionally, this mutation has been described in five unrelated families and was observed to result in aberrant splicing, including coding exon 3 skipping (also referred to as exon 5 skipping in the literature: Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). Based on the available evidence, this alteration is classified as a disease-causing mutation.
GeneDx RCV000047713 SCV000210069 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.211A>G at the cDNA level, p.Arg71Gly (R71G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). Using alternate nomenclature, this pathogenic variant has been previously published as BRCA1 330A>G. This variant is predicted by multiple in silico splicing programs to significantly reduce or destroy the natural splice donor site, and lead to aberrant gene splicing. Importantly, both Vega et al. (2001) and Santos et al (2009) confirmed via RT-PCR (peripheral blood derived mRNA) that this variant results in the loss of 22 nucleotides in exon 5 and a subsequent premature stop codon due to a cryptic splice donor site. BRCA1 c.211A>G has been described as a pathogenic Spanish founder variant in association with familial breast and/or ovarian cancer (Vega 2001, Santos 2009, Gabald? Barrios 2017). Although the nucleotide substitution results in the change of an Arginine to a Glycine at codon 71, and is called Arg71Gly in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA1 c.211A>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, an adenine (A) at base 211, is conserved across species. Based on currently available evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047713 SCV000296343 pathogenic not provided 2019-06-04 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Located in potentially important domain of the protein. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019263 SCV000325237 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000019263 SCV000488382 pathogenic Breast-ovarian cancer, familial 1 2016-03-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131899 SCV000537653 pathogenic Hereditary cancer-predisposing syndrome 2020-09-15 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 71 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional RNA studies have shown that this variant causes exon 4 skipping or use of a cryptic site in exon 4, resulting in F46_R71del or premature truncation, C64\* (PMIDs: 22505045, 20215541, 11385711). This variant has been reported in individuals affected with familial breast/ovarian cancer (PMID: 31131967, 29446198, 28664506, 27836010, 26246475, 25716084, 27081505, 23683081, 23199084, 20215541, 20104584, 20103620, 19123044, 18159056, 16403807, 11385711). This variant has been identified in 1/249744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics RCV000469732 SCV000540947 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genologica Medica RCV000019263 SCV000577917 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000195359 SCV000588028 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508177 SCV000602724 pathogenic not specified 2018-07-02 criteria provided, single submitter clinical testing The BRCA1 c.211A>G; p.Arg71Gly variant (rs80357382), also known as 330A>G, has been described in multiple families with history of breast and/or ovarian cancers (Diez 1999, Sanz 2010, Vega 2001). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 17693), and is only observed on 1 allele in the Genome Aggregation Database. This variant is two nucleotide from the canonical splice site, and computational algorithms (Alamut v.2.11) predict the weakening or loss of the splice donor. Consistent with this, functional characterization of the variant indicates aberrant splicing of the BRCA1 transcript, resulting in the introduction of a premature termination codon (Houdayer 2012, Sanz 2010, Vega 2001). Based on available information, this variant is considered pathogenic. References: Diez O et al. BRCA1 mutation analysis in 83 Spanish breast and breast/ovarian cancer families. Int J Cancer. 1999; 83(4):465-9. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012; 33(8):1228-38. Sanz D et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010; 16(6):1957-67. Vega A et al. The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat. 2001; 17(6):520-1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195359 SCV000698917 pathogenic Hereditary breast and ovarian cancer syndrome 2020-12-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.211A>G (p.Arg71Gly) 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. As a variant located within the exonic-splice region close to the intronic splice donor site, several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least two publications report experimental evidence that this variant affects mRNA splicing (example, Vega_2001, Santos_2009). The variant allele was found at a frequency of 4e-06 in 249844 control chromosomes. c.211A>G 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. At-least one mutually exclusive co-occurrence with another pathogenic variant(s) has been reported in the UMD database (BRCA2 c.2701delC, p.Ala902LeufsX2). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of function as evaluated in a high throughput system that used saturation genome editing to assess homology directed repair (HDR) activity (Findlay_2018). Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000195359 SCV000839310 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763009 SCV000893454 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659722 SCV001877342 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
OMIM RCV000019263 SCV000039551 pathogenic Breast-ovarian cancer, familial 1 2003-10-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019263 SCV000053620 pathogenic Breast-ovarian cancer, familial 1 2012-10-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019263 SCV000144658 pathogenic 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 RCV000195359 SCV000587031 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Center of Medical Genetics and Primary Health Care RCV000469732 SCV000978253 pathogenic Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria The BRCA1 variant p.Arg71Gly is a known pathogenic missense mutation in exon 5 that is found in the Zinc finger domain, RING/FYVE/PHD-type (E10-85E aa). It is now recognized to bind DNA, RNA, protein and/or lipid substrates (PMID: 17210253). It is found in a mutational hotspot including 28 pathogenic frameshift and nonsense variants (PM1 Pathogenic Moderate). It was conformed via RT-PCR that this variant results in the loss of 22 nucleotides in exon 5 and a subsequent premature stop codon due to a cryptic splice donor site (PMID: 11385711; 19123044) (PS3 Pathogenic Strong). The allele frequency in GnomAD exomes is 0.000004 which is less the threshold 0.0001 for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). Three different pathogenic missense changes at the same amino acid residue (chr17:41258473C>A (Arg71Ile); chr17:41258473C>G (Arg71Thr); chr17:41258473C>T (Arg71Lys)) have been reported in ClinVar (PM5 Pathogenic Moderate). 10 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT versus 1 benign prediction from DEOGEN2 support its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV001161539.1) (PP5 Pathogenic Supporting). In our study this variant was found in a 36-year-old female with unilateral breast cancer and a family history of breast cancer. Therefore, this variant was classified as a Pathogenic.
Brotman Baty Institute,University of Washington RCV000019263 SCV001241677 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047713 SCV001553303 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000047713 SCV001930239 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000047713 SCV001956283 pathogenic not provided 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.