17-43063903-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5123C>A(p.Ala1708Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1708P) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5123C>A | p.Ala1708Glu | missense_variant | 17/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5123C>A | p.Ala1708Glu | missense_variant | 17/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251312Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135846
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727164
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:15Other:1
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Apr 09, 2020 | This variant has been reported in the literature in multiple individuals and families with breast and/or ovarian cancer, and has been shown to segregate with disease (Lovelock 2006, Torres 2007, Millevoi 2010, Sagi 2011). This variant has an overall allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, this variant is interpreted as pathogenic. PS4-moderate; PP1; PP3 - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 04, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PS3; PP3; PP1; Expert panel - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 29, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces alanine with glutamic acid at codon 1708 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). RNA studies have reported varying degrees of exon 17 (BIC exon 18) skipping (PMID: 19404736, 20215541, 26780556). Functional studies have reported this variant impacts BRCA1 function in mammalian transcription activation assays (PMID: 15923272, 11157798, 17305420), complementation of BRCA1-deficient embryonic stem cells (PMID: 19770520, 23867111), a haploid cell proliferation assay (PMID: 30209399) and homology-directed repair and chromosome aberration assays (PMID: 34855882). This variant has been observed as a recurrent mutation in Spanish hereditary breast and ovarian cancer families (PMID: 10737987, 12955716, 23479189, 28477318) and in individuals and families affected with breast and ovarian cancer in other populations (PMID: 7939630, 9523200, 11157798, 15340362, 17080309, 19404736, 30606148, 30287823, 33471991, 34196900). This variant has been shown to segregate with disease in three pedigrees (PMID: 15923272). This variant has been identified in 5/251312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5242 C>A; This variant is associated with the following publications: (PMID: 21702907, 21447777, 21520273, 22044689, 21922593, 17305420, 24742220, 17924331, 12400015, 27286788, 28758972, 28680148, 28477318, 30606148, 28781887, 23867111, 20516115, 20378548, 20215541, 23233716, 11802208, 11157798, 17925560, 19404736, 9159158, 8942979, 8751436, 23199084, 23479189, 15923272, 18036263, 8872468, 18680205, 19770520, 25782689, 15235020, 7939630, 21990134, 25748678, 26071757, 26656232, 25085752, 27742776, 26780556, 27802165, 27272900, 27836010, 27533489, 28339459, 28283652, 28127413, 17080309, 28398198, 28918466, 27463008, 28528518, 28985766, 29021639, 29560538, 21063910, 29884136, 29088781, 29086229, 29433453, 30541753, 29321669, 29907814, 30209399, 30103829, 30630528, 30262796, 29446198, 30322717, 30765603, 27356891, 25525159, 32733560, 33067490, 31589614, 32341426, 32885271, 33087888, 30787465, 33087929) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 05, 2020 | The BRCA1 c.5123C>A; p.Ala1708Glu variant (rs28897696), also known as 5242C>A, is a common recurrent variant in the Spanish population (de la Hoya 2002, Futreal 1994, Sanz 2010), and functional assays have confirmed this variant causes loss of function (Findlay 2018, Sanz 2010). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 55407). It is found in the general population with a low overall allele frequency of 0.002% (5/251312 alleles) in the Genome Aggregation Database. The alanine at codon 1708 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: de la Hoya M et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002 Feb 1;97(4):466-71. Findlay GM et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct;562(7726):217-222. Futreal PA et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120-2. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 09, 2019 | The BRCA1 c.5123C>A (p.Ala1708Glu) variant has been reported in the published literature in individuals and families affected with breast or ovarian cancer (PMID: 28477318 (2017), 23233716 (2013), 22399190 (2012), 17924331 (2007), 12955716 (2003), 11802208 (2002)). Additionally, functional studies indicate that this variant has a damaging effect on BRCA1 protein structure and function and may result in aberrant BRCA1 mRNA splicing (PMID: 19404736 (2010), 20516115 (2010), 18036263 (2007), 12400015 (2002), 11157798 (2001)). The frequency of this variant in the general population, 0.000058 (2/34580 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | Considered pathogenic based on Myriad report from BB4536. NVA Still recommended. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1708 of the BRCA1 protein (p.Ala1708Glu). This variant is present in population databases (rs28897696, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 15923272, 17080309, 19404736, 21063910). It has also been observed to segregate with disease in related individuals. This variant is also known as 5242C>A. ClinVar contains an entry for this variant (Variation ID: 55407). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11157798, 15923272, 17305420, 19770520, 20516115, 25748678). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 26, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2019 | The p.Ala1708Glu variant in BRCA1 has been reported 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 (Futreal 1994, Greenman 1998, Blesa 2000, de la Hoya 2002, Infante 2006, Torres 2007, Laitman 2011, Sagi 2011, Laitman 2012, Rodriguez 2012, de Juan 2013, Hernandez 2014). It has also been identified in 2/34580 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In vitro functional studies provide some evidence that the p.Ala1729Glu variant may cause skipping of exon 18 (Millevoi 2010, Sanz 2010). In addition, this variant was classified as Pathogenic on Aug 10, 2015 by the ClinGen-approved ENIGMA Expert Panel (ClinVar SCV000244385.1). In summary, the p.Ala1729Glu variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1_Moderate. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 22, 2021 | The p.A1708E pathogenic mutation (also known as c.5123C>A), located in coding exon 16 of the BRCA1 gene, results from a C to A substitution at nucleotide position 5123. The alanine at codon 1708 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in numerous high-risk breast/ovarian cancer families (Fernandez-Lopez JC et al. Hum Genomics 2019 01;13(1):3; Abdel-Razeq H et al. J Oncol 2020 Jul;2020:8362179; Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb;10:353-60; Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507; Capanu M et al. Genet. Epidemiol. 2011 Jul;35:389-97; Gabaldó Barrios X et al. Fam. Cancer. 2017 Oct;16:477-489) and has been described as a founder mutation in the Colombian, Spanish, and Sephardic Jewish populations (Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Janavicius R. EPMA J. 2010 Sep;1:397-412; Sagi M et al. Fam. Cancer. 2011 Mar;10:59-63). Multiple functional studies have classified this alteration as deleterious (Findlay GM et al. Nature 2018 10;562(7726):217-222; Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lovelock PK et al. J. Med. Genet. 2006 Jan;43:74-83). A statistical algorithm based on personal and family history of cancer has also classified this alteration as pathogenic (Pruss D et al. Breast Cancer Res. Treat. 2014 Aug;147:119-32). In addition, p.A1708E was classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Of note, this alteration is also referred to as 5242C>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 02, 2023 | This missense variant replaces alanine with glutamic acid at codon 1708 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). RNA studies have reported varying degrees of exon 17 (BIC exon 18) skipping (PMID: 19404736, 20215541, 26780556). Functional studies have reported this variant impacts BRCA1 function in mammalian transcription activation assays (PMID: 15923272, 11157798, 17305420), complementation of BRCA1-deficient embryonic stem cells (PMID: 19770520, 23867111), a haploid cell proliferation assay (PMID: 30209399) and homology-directed repair and chromosome aberration assays (PMID: 34855882). This variant has been observed as a recurrent mutation in Spanish hereditary breast and ovarian cancer families (PMID: 10737987, 12955716, 23479189, 28477318) and in individuals and families affected with breast and ovarian cancer in other populations (PMID: 7939630, 9523200, 11157798, 15340362, 17080309, 19404736, 30606148, 30287823, 33471991, 34196900). This variant has been shown to segregate with disease in three pedigrees (PMID: 15923272). This variant has been identified in 5/251312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 18, 2022 | - - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 02, 2022 | - - |
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | - | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 21, 2021 | Invasive ductal carcinoma EST= - PRO = - HER2 = - KI = 75% - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at