ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5123C>A (p.Ala1708Glu) (rs28897696)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413608 SCV000492454 pathogenic Neoplasm of the breast criteria provided, single submitter research
Ambry Genetics RCV000131831 SCV000186886 pathogenic Hereditary cancer-predisposing syndrome 2017-07-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Good segregation with disease (lod 1.5-3 = 5-9 meioses),Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s)
Baylor Genetics RCV000457403 SCV000540948 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077599 SCV000145320 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131831 SCV000537686 pathogenic Hereditary cancer-predisposing syndrome 2016-06-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077599 SCV000326160 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077599 SCV000677657 pathogenic Breast-ovarian cancer, familial 1 2017-01-26 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077599 SCV000744598 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167826 SCV000591583 pathogenic Hereditary breast and ovarian cancer syndrome 2012-09-11 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077599 SCV000733598 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000077599 SCV000212006 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077599 SCV000244385 pathogenic Breast-ovarian cancer, familial 1 2015-08-10 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
GeneDx RCV000048802 SCV000210200 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5123C>A at the cDNA level, p.Ala1708Glu (A1708E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCG>GAG). Using alternate nomenclature, this variant has been previously published as BRCA1 5242C>A. This variant was observed in numerous breast/ovarian cancer families and reported as a recurrent pathogenic variant in Spain, Columbia, and in other Hispanic populations (Diez 2003, Vogel 2007, Janavicus 2010, de Juan Jimenez 2013, Weitzel 2013, Hernandez 2014, Torres 2017). RNA and minigene assays have demonstrated that BRCA1 c.5123C>A causes either complete or partial exonic skipping (Millevoi 2010, Sanz 2010, Quiles 2016). When present in a full-length transcript, functional assays interrogating the impact of BRCA1 Ala1708Glu on transcription activity, protease sensitivity, peptide binding, thermodynamic stability, cellular localization, centrosome amplification, cell growth and survival, homologous recombination, and cisplatin sensitivity have confirmed the pathogenic nature of this variant (Chapman 1996, Monteiro 1996, Humphrey 1997, Vallon-Christersson 2001, Lovelock 2006, Lee 2010, Rowling 2010, Bouwman 2013, Gaboriau 2015, Thouvenot 2016, Anantha 2017). In addition, this variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. BRCA1 Ala1708Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Ala1708Glu is located in the BRCT1 domain and a region that interacts with multiple proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Genologica Medica RCV000077599 SCV000577935 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000167826 SCV000699205 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-26 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5123C>A (p.Ala1708Glu) variant involves the alteration of a conserved nucleotide located in the BRCT domain of the protein (InterPro). 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 3/120626 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in several HBOC patients indicating pathogenicity. Additionally, a functional study demonstrated the variant to result in inappropriate skipping of the entire exon 18, to reduce structural stability, phosphopeptide binding and transcription activity further supporting a deleterious impact. Several variants affecting the same codon are reported in UMD/HGMD/ClinVar such as UMD: c.5123C>G (p.Ala1708Gly), c.5123C>T (p.Ala1708Val), c.5123delC (p.Ala1708GlyfsX6), c.5124G>A (p.Ala1708Ala), c.5122G>C (p.Ala1708Pro) indicating the variant to be located in a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000167826 SCV000076815 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 1708 of the BRCA1 protein (p.Ala1708Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs28897696, ExAC 0.009%). This variant has been reported in numerous individuals and families affected with breast and ovarian cancer, and has been shown to co-segregate with disease (PMID: 15923272, 19404736, 17080309, 21063910). It is also known as 5242C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55407). This variant is located in the BRCT domain, which is important for the tumor suppressor function of the BRCA1 protein (PMID: 20516115). Experimental studies have shown that this variant alters BRCA1 mRNA splicing, and has a deleterious impact on BRCA1 transcriptional transactivation and DNA double-strand break repair activities (PMID: 11157798, 15923272, 17305420, 19404736, 20516115). For these reasons, it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000167826 SCV000605743 pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-21 criteria provided, single submitter clinical testing The p.Ala1729Glu (also reported as p.Ala1708Glu) variant in BRCA1 has been repor ted in more than 40 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in at least 5 affected relatives from 3 families (F utreal 1994, Greenman 1998, Blesa 2000, de la Hoya 2002, Infante 2006, Torres 20 07, Laitman 2011, Sagi 2011, Laitman 2012, Rodriguez 2012, de Juan 2013, Hernand ez 2014). It has also been identified in 2/66310 European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org, dbSNP rs3865763 92, rs28897696); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. In vitro functional studies provid e some evidence that the p.Ala1729Glu variant may cause skipping of exon 18 (Mil levoi 2010, Sanz 2010). In addition, this variant was classified as Pathogenic o n Aug 10, 2015 by the ClinGen-approved ENIGMA Expert Panel (ClinVar SCV000244385 .1). In summary, the p.Ala1729Glu variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC.
Mendelics RCV000167826 SCV000839216 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000048802 SCV000806966 pathogenic not provided 2017-08-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048802 SCV000296313 pathogenic not provided 2015-03-20 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167826 SCV000587466 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077599 SCV000109402 pathogenic Breast-ovarian cancer, familial 1 2013-01-29 no assertion criteria provided clinical testing

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