ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.211A>G (p.Arg71Gly) (rs80357382)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195359 SCV000075726 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-03 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 2018-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 2015-04-02 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 2017-02-04 criteria provided, single submitter clinical testing
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

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