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

dbSNP: rs1800751

Total submissions: 15

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, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031251	SCV000564312	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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 Diagnostics, LLC DBA Color Health	RCV000574861	SCV000903563	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-05	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). It has been reported that there is no wild type transcript produced from the mutant allele (ClinVar SCV000665890.4). Cells transfected with the mutant allele show defective BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in many individuals affected with breast and ovarian cancer (PMID: 12955716, 14517958, 17020472, 17453335, 19452558, 20522429, 23536787, 27495310, 29470806) and has been shown to segregate with disease in five unrelated families (PMID: 34597585). 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 Pathogenic.
Invitae	RCV001390965	SCV001592874	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-06	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs1800751, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in skipping of exon 22 and introduces a premature termination codon (PMID: 20522429, 22505045, 27495310). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17020472, 19452558, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 37670). This variant is also known as 5553C>G. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 14517958, 17020472, 17453335, 20522429, 27495310, 29470806). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1812 of the BRCA1 protein (p.Pro1812Ala). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000484398	SCV002048058	pathogenic	not provided	2021-07-16	criteria provided, single submitter	clinical testing	The BRCA1 c.5434C>G; p.Pro1812Ala variant (rs1800751), also known as 5553C>G, is reported in the literature in several individuals with a personal and family history of hereditary breast and ovarian cancer and the variant is reported to segregate with disease in two families (Diez 2003, Gaildrat 2010, Jarhelle 2016, Konstantopoulou 2008, Laitman 2011, Martinez-Ferrandis 2003, Stavropoulou 2013). RNA studies in patient cells and in vitro splicing assays have shown that this variant causes skipping of this exon leading to a truncated protein product and disrupting a functional domain (Gaildrat 2010, Jarhelle 2016). This variant is also described as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 37670). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic References: Diez O et al. Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat. 2003 Oct;22(4):301-12. PMID: 12955716. Gaildrat P et al. The BRCA1 c.5434C>G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements. J Med Genet. 2010 Jun;47(6):398-403. PMID: 20522429. Jarhelle E et al. Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort. Fam Cancer. 2017 Jan;16(1):1-16. PMID: 27495310. Kaufman B et al. The P1812A and P25T BRCA1 and the 5164del4 BRCA2 mutations: occurrence in high-risk non-Ashkenazi Jews. Genet Test. 2006 Fall;10(3):200-7. PMID: 17020472. Konstantopoulou I et al. Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients. Breast Cancer Res Treat. 2008 Feb;107(3):431-41. PMID: 17453335. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. PMID: 20960228. Martinez-Ferrandis JI et al. Mutational analysis of BRCA1 and BRCA2 in Mediterranean Spanish women with early-onset breast cancer: identification of three novel pathogenic mutations. Hum Mutat. 2003 Nov;22(5):417-8. PMID: 14517958. Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196. PMID: 29470806.
Genetics and Molecular Pathology, SA Pathology	RCV000031251	SCV002761613	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-09-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000484398	SCV003811688	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031251	SCV000053855	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031251	SCV000145514	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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, susceptibility to, 1		no assertion provided	in vitro