ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5434C>G (p.Pro1812Ala) (rs1800751)

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Total submissions: 12
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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 pathogenic Hereditary cancer-predisposing syndrome 2020-07-15 criteria provided, single submitter clinical testing The c.5434C>G variant (also known as p.P1812A), located in coding exon 21 of the BRCA1 gene, results from a C to G substitution at nucleotide position 5434. The proline at codon 1812 is replaced by alanine, an amino acid with highly similar properties. This alteration has been detected in many breast and ovarian cancer cohorts (Martínez-Ferrandis JI et al. Hum. Mutat. 2003 Nov;22:417-8; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Kaufman B et al. Genet. Test. 2006;10:200-7; Stavropoulou AV et al. PLoS ONE, 2013 Mar;8:e58182; Jarhelle E et al. Fam. Cancer. 2017 01;16:1-16; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). Numerous studies have reported that this alteration causes skipping of coding exon 21 (also called exon 23 in the literature) and although one study shows semi-quantitative data indicating the splice defect may be leaky, another unpublished study shows that there is no wildtype transcript produced from the altered allele (Ambry internal data; Gaildrat P et al. J. Med. Genet. 2010 Jun;47:398-403; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Jarhelle E et al. Fam. Cancer. 2017 01;16:1-16; personal communication). Using the BDGP and ESEfinder splice site prediction tools, this alteration is to predicted to strengthen a cryptic splice acceptor site that becomes stronger than the native splice acceptor site; however, there is also functional evidence that this variant negatively impacts a splice enhancer site (Gaildrat P et al. J. Med. Genet. 2010 Jun;47:398-403). In a haploid cell survival assay, which can measure both RNA and protein effects, this variant was non-functional with evidence supporting a splice defect (Findlay GM et al. Nature, 2018 10;562:217-222). Several functional studies have been conducted on the missense substitution and have shown modest defects in transcription activation, thermostability and affinity for BRIP1 binding (Kaufman B et al. Genet. Test. 2006;10:200-7; Drikos I et al. Proteins. 2009 Nov;77:464-76​). Based on internal structural analysis, this amino acid substitution will result in greater local structural destabilization than other nearby pathogenic alterations (Clapperton JA et al. Nat. Struct. Mol. Biol. 2004 Jun;11:512-8; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV000574861 SCV000903563 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-19 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 1812 of the BRCA1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant also causes a C>G nucleotide substitution at nucleotide 5434 in exon 22 of the BRCA1 gene. RNA studies have reported that this variant caused the out-of-frame skipping of exon 22 that disrupted the BRCT domain in the encoded protein (PMID: 20522429, 21673748, 27495310). A functional study that also responded to RNA expression and stability showed that this variant caused the loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in individuals and families affected with breast and ovarian cancer (PMID: 12955716, 14517958, 17020472, 17453335, 19452558, 20522429, 23536787, 27495310). This variant has also been identified in 1/251488 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 Likely Pathogenic.
Invitae RCV001390965 SCV001592874 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 1812 of the BRCA1 protein (p.Pro1812Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with breast and/or ovarian cancer, and to segregate with disease in two families (PMID: 14517958, 17020472, 17453335, 20522429, 27495310, 29470806). This variant is also known as 5553C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37670). Experimental studies have shown that this variant disrupts mRNA splicing and induces skipping of exon 22 (also known as exon 23) (PMID: 20522429, 22505045, 27495310). This variant has also been reported to affect BRCA1 protein function (PMID: 17020472, 19452558, 30209399). For these reasons, this variant has been classified as Pathogenic.
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
Brotman Baty Institute,University of Washington RCV000031251 SCV001243324 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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