ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5434C>G (p.Pro1812Ala) (rs1800751)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031251 SCV000326312 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031251 SCV000564312 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000484398 SCV000564753 likely pathogenic not provided 2017-08-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5434C>G at the cDNA level, p.Pro1812Ala (P1812A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). Using alternate nomenclature, this variant would be defined as BRCA1 5553C>G. This variant has been observed in several individuals with a personal and family history consistent with Hereditary Breast and Ovarian Cancer syndrome, segregating with disease in two kindreds (Martinez-Ferrandis 2003, Diez 2003, Kaufman 2006, Gaildrat 2010, Laitman 2011, Stavropoulou 2013, Jarhelle 2016). RNA and minigene assays have demonstrated that this variant causes skipping of exon 22, published as exon 23, in most transcripts, leading to a truncated protein product and disrupting the second BRCT domain (Gaildrat 2010, Jarhelle 2016). When present in a full-length transcript, BRCA1 Pro1812Ala has been found to cause a slight reduction in transcriptional activity, protein binding capacity, and thermostability (Kaufman 2006, Drikos 2009). Although the nucleotide substitution results in the change of a Proline to an Alanine at codon 1812, and may also be called Pro1812Ala in the literature, we are using 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.5434C>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The nucleotide which is altered, a cytosine (C) at base 5434, is conserved through mammals. Based on current evidence, we consider BRCA1 c.5434C>G to be a likely pathogenic variant.
Genologica Medica RCV000031251 SCV000577941 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574861 SCV000665890 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000574861 SCV000903563 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031251 SCV000053855 uncertain significance Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031251 SCV000145514 uncertain significance Breast-ovarian cancer, familial 1 2009-06-05 no assertion criteria provided clinical testing
Department of Medical Genetics,University Hospital of North Norway RCV000031251 SCV000301440 likely pathogenic Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496797 SCV000587508 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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