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

dbSNP: rs80357382

Total submissions: 33

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, susceptibility to, 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195359	SCV000075726	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 71 of the BRCA1 protein (p.Arg71Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357382, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 12014998, 20215541). It is commonly reported in individuals of Spanish ancestry (PMID: 11385711, 23683081, 27081505). This variant is also known as 330A>G. ClinVar contains an entry for this variant (Variation ID: 17693). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 2316185, 11320250, 16403807, 20103620, 21725363). Studies have shown that this missense change results in activation of a cryptic splice site and exon 4 skipping and introduces a premature termination codon (PMID: 2173504, 11385711, 19123044, 20215541; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131899	SCV000186954	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-23	criteria provided, single submitter	clinical testing	The c.211A>G pathogenic mutation (also known as p.R71G), 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 (Ambry internal data; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). 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 10;562(7726):217-222). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a disease-causing mutation.
GeneDx	RCV000047713	SCV000210069	pathogenic	not provided	2022-02-07	criteria provided, single submitter	clinical testing	Exonic splice variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Vega 2001, Santos 2009); Published functional studies demonstrate a damaging effect: classified as loss of function based on results of a cell survival assay and multifactorial likelihood analysis suggests this variant is pathogenic (Findlay 2018, Parsons 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 330A>G; This variant is associated with the following publications: (PMID: 21725363, 27083775, 28477318, 28664506, 20215541, 23161852, 15235020, 11320250, 10508480, 21735045, 26246475, 25823446, 19123044, 25782689, 26913838, 22505045, 28453507, 28127413, 27081505, 27836010, 30240327, 29884136, 30103829, 20103620, 30209399, 29446198, 11385711, 30995943, 30720243, 30606148, 30630528, 31131967, 31454914, 25525159, 33087888, 31589614, 32341426, 32719484, 33558524, 20104584, 24389207, 27535533)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047713	SCV000296343	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	The BRCA1 c.211A>G (p.Arg71Gly) variant has been reported in the published literature in multiple individuals with breast cancer and it is described as a founder mutation in the Spanish population (PMIDs: 11385711 (2001) and 20215541 (2010)). In a large-scale breast cancer association study, the variant was observed among the breast cancer cases and not in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). Published functional studies have shown that this variant has a deleterious effect on BRCA1 mRNA splicing (PMIDs: 11385711 (2001), 20215541 (2010), 21735045 (2012), and 22505045 (2012)). In addition, this variant has been characterized as being pathogenic in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000004 (1/249744 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019263	SCV000325237	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000019263	SCV000488382	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131899	SCV000537653	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	This variant is located in exon 4 near the intron 4 splice donor site. RNA analyses have shown that this variant results in out-of-frame splicing involving exon 4 that is predicted to cause an absent or non-functional protein product (PMID: 11385711, 20215541, 22505045). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer (PMID: 10508480, 12955716, 18159056, 19123044, 20104584, 23683081, 25716084, 28664506, 28985766, 29088781, 30606148, 33471991; Leiden Open Variation Database DB-ID BRCA1_000059), and has been identified in 129 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). Haplotype analysis suggests that this variant is a founder mutation originating in Northern Spain (PMID: 11385711, 12014998). This variant has been reported to segregate with disease with a likelihood ratio for pathogenicity of 383.2656 (PMID: 31131967). 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, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000195359	SCV000588028	pathogenic	Hereditary breast 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 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 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, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-12-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000047713	SCV002017851	pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing
DASA	RCV000019263	SCV002107091	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID 30209399; 11385711; 19123044). - PS3_moderate.The c.211A>G;p.(Arg71Gly) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17693; PMID: 12014998) - PS4. The variant is present at low allele frequencies population databases (rs80357382 – gnomAD 0.00004004%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID:185705; ClinVar ID:54471; ClinVar ID :267512) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 12014998; 20215541) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000019263	SCV002512509	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-07-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM5 moderate, PP1 strong, PP3 supporting
Genetics Program, Instituto Nacional de Cancer	RCV000195359	SCV002515220	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131899	SCV002538094	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Baylor Genetics	RCV000019263	SCV004212728	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-22	criteria provided, single submitter	clinical testing
OMIM	RCV000019263	SCV000039551	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-10-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019263	SCV000053620	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-10-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019263	SCV000144658	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000047713	SCV001956283	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000019263	SCV004244183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000019263	SCV005061328	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control
PreventionGenetics, part of Exact Sciences	RCV004758595	SCV005361050	pathogenic	BRCA1-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The BRCA1 c.211A>G variant is predicted to result in the amino acid substitution p.Arg71Gly. This variant has been reported to be causative for breast/ovarian cancer, and appears to be a Spanish founder variant (Díez et al. 1999. PubMed ID: 10508480; Vega et al. 2002. PubMed ID: 12014998; Sanz et al. 2010. PubMed ID: 20215541; Felix et al. 2014. PubMed ID: 27081505). This variant has been shown in vitro to cause exon skipping by introducing a cryptic splice site (Houdayer et al. 2012. PubMed: 22505045), and cells harboring this variant are more sensitive to radiation and showed genomic instability compared to cells with control variants (Cochran et al. 2015. PubMed: 26246475). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/17693/). This variant is interpreted as pathogenic.