ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.213-12A>G (rs80358163)

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Total submissions: 18
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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) RCV000031031 SCV001161543 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 = 1
Invitae RCV000167772 SCV000075739 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-17 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (rs80358163, ExAC no frequency). This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 9805131, 21348412, 19563646, 23479189). It is also known as IVS5-12A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37450). Experimental studies have shown that this intronic change creates a novel cryptic splice site resulting in the addition of 11 nucleotides to the BRCA1 mRNA (PMID: 9805131). This is predicted to create a premature translational stop signal (p.Arg71Serfs*21), and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131900 SCV000186955 pathogenic Hereditary cancer-predisposing syndrome 2019-02-27 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Other strong data supporting pathogenic classification;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Michigan Medical Genetics Laboratories,University of Michigan RCV000031031 SCV000195879 pathogenic Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000047726 SCV000210070 pathogenic not provided 2017-10-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.213-12A>G or IVS4-12A>G and consists of an A>G nucleotide substitution at the -12 position of intron 4 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 332-12A>G or IVS5-12A>G. This variant has been observed in association with breast and ovarian cancer, including a large family in which this variant segregated with disease in multiple affected individuals (Hoffman 1998, Meindl 2002, Thirthagiri 2008, Foretova 2010, de Juan Jimenez 2013, Kang 2015). Although in silico splicing models predict no effect or are uninformative, RNA studies identified that this variant results in a cryptic splice site that adds 11 nucleotides upstream of exon 5, causing a frameshift that results in a premature stop codon (Hoffman 1998, Menéndez 2012). BRCA1 c.213-12A>G was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The adenine (A) nucleotide that is altered is not conserved. Based on current evidence, we consider this variant to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000167772 SCV000271314 pathogenic Hereditary breast and ovarian cancer syndrome 2016-01-19 criteria provided, single submitter clinical testing The c.213-12A>G variant in BRCA1 has been reported in >25 individuals with BRCA1 -associated cancers and segregated with disease in 4 affected relatives from 2 f amilies (Dong 1998, Hoffman 1998, Meindl 2002, Thirthagiri 2008, Kast 2012, de J uan Jimenez 2013, Brohet 2014,Breast Cancer Information Core (BIC) database). Th is variant was absent from large population studies. In vitro functional studies provide evidence that the c.213-12A>G variant introduces a cryptic splice site, causing an additional 11 nucleotides to be retained and leading to a frameshift , which alters the protein?s amino acid sequence beginning at position 71 and le ads to a premature termination codon 21 amino acids downstream (Hoffman 1998, Me nendez 2012). This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established dise ase mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this v ariant meets our criteria to be classified as pathogenic for HBOC in an autosoma l dominant manner based upon segregation studies, absence from controls, and fun ctional evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047726 SCV000296403 pathogenic not provided 2015-11-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031031 SCV000325255 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031031 SCV000487940 pathogenic Breast-ovarian cancer, familial 1 2015-12-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505888 SCV000602725 pathogenic not specified 2017-02-10 criteria provided, single submitter clinical testing
Color RCV000131900 SCV000683015 pathogenic Hereditary cancer-predisposing syndrome 2020-03-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000167772 SCV000698920 pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-17 criteria provided, single submitter clinical testing Variant summary: The c.213-12A>G variant affects a non-conserved intronic nucleotide. One in-silico tool predicts disease-causing outcome for this variant. 3/5 programs in Alamut predict that this variant create a novel 3' acceptor splicing site, which has been confirmed by RT-PCR and sequencing. This novel splicing site results in incorporation of 11 bases of intron 5, leading to a frameshift in the codon sequence, which is predicted to result in truncated protein, p.Arg71SerfsX21. This variant is not found in 121156 control chromosomes. However, it has been reported in at least 19 HBOC patients. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000047726 SCV000806910 pathogenic not provided 2017-06-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031031 SCV000053625 pathogenic Breast-ovarian cancer, familial 1 2012-06-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031031 SCV000144671 pathogenic Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167772 SCV000587039 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031031 SCV000733677 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785201 SCV000923769 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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