Submissions for variant NM_007294.4(BRCA1):c.5123C>A (p.Ala1708Glu)

dbSNP: rs28897696

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077599	SCV000244385	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167826	SCV000076815	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000131831	SCV000186886	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000048802	SCV000210200	pathogenic	not provided	2020-02-12	criteria provided, single submitter	clinical testing	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)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048802	SCV000296313	pathogenic	not provided	2019-09-09	criteria provided, single submitter	clinical testing	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077599	SCV000326160	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413608	SCV000492454	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000131831	SCV000537686	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000457403	SCV000540948	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000077599	SCV000577935	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167826	SCV000605743	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000077599	SCV000677657	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167826	SCV000699205	pathogenic	Hereditary breast 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077599	SCV000744598	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000167826	SCV000839216	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000077599	SCV001434306	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-09	criteria provided, single submitter	clinical testing	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
Johns Hopkins Genomics, Johns Hopkins University	RCV000077599	SCV001469046	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-12-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000048802	SCV001473240	pathogenic	not provided	2020-10-05	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000131831	SCV002537813	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000048802	SCV003817982	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149709	SCV003838233	pathogenic	Breast and/or ovarian cancer	2022-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077599	SCV004212745	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077599	SCV004817587	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-08	criteria provided, single submitter	clinical testing	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077599	SCV005045973	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PS3; PP3; PP1; Expert panel
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000167826	SCV005061362	pathogenic	Hereditary breast ovarian cancer syndrome	2024-06-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077599	SCV000109402	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-01-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077599	SCV000145320	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000077599	SCV000212006	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167826	SCV000587466	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000048802	SCV000591583	pathogenic	not provided		no assertion criteria provided	clinical testing	Considered pathogenic based on Myriad report from BB4536. NVA Still recommended.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077599	SCV000733598	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758631	SCV000806966	pathogenic	BRCA1-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The BRCA1 c.5123C>A variant is predicted to result in the amino acid substitution p.Ala1708Glu. This variant (also known as c.5242C>A) has been reported in numerous families of Spanish origin with a history of breast and ovarian cancer (de Juan Jiménez et al. 2013. PubMed ID: 23479189; Janavicius 2010. PubMed ID: 23199084; Table 2, Díez et al. 2003. PubMed ID: 12955716). Functional studies have also reported that this variant impacts protein stability (Rowling et al. 2010. PubMed ID: 20378548) and results in skipping of exon 18 (Millevoi et al. 2010. PubMed ID: 19404736). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. In ClinVar, it is reported as pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/55407/). This variant is interpreted as pathogenic.
Brotman Baty Institute, University of Washington	RCV000077599	SCV001237651	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001579293	SCV001805826	pathogenic	Breast carcinoma	2021-08-21	no assertion criteria provided	clinical testing	Invasive ductal carcinoma EST= - PRO = - HER2 = - KI = 75%
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000048802	SCV001956544	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077599	SCV004243949	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000077599	SCV005061293	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control