ClinVar Miner

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

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Total submissions: 21
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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 2019-12-23 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 Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
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 RCV000131899 SCV000537653 pathogenic Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000195359 SCV000698917 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The c.211A>G variant affects a conserved nucleotide, resulting in amino acid change from Arg to Gly. 5/5 in-silico tools predict damaging outcome for this variant. The variant lies two nucleotides upstream from the exon-intron junction and is predicted to affect normal splicing by 4/5 in silico programs via Alamut. Functional studies show that this variant leads to disruption of normal splicing (Vega 2001, Santos 2009). This variant is not found in approximately 118218 control chromosomes but has been reported in several HBOC patients/families including evidence of cosegregation with disease (Vega 2001). It has also been reported in several individuals undergoing clinical BRCA1/2 testing in clinical databases. Several clinical labs/databases have classified this variant as pathogenic. Taken together, this variant has been 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
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 (Table 1).
Brotman Baty Institute,University of Washington RCV000019263 SCV001241677 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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