Submissions for variant NM_007294.4(BRCA1):c.5175A>G (p.Glu1725=)

gnomAD frequency: 0.00002  dbSNP: rs191373374

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000410590	SCV000578251	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx	RCV000123933	SCV000167320	benign	not specified	2014-03-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163992	SCV000214593	likely benign	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001082311	SCV000262479	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000410590	SCV000488591	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163992	SCV000683268	benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588977	SCV000699217	likely benign	not provided	2017-03-17	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5175A>G (p.Glu1725Glu) variant involves the alteration of a conserved nucleotide causing a synonymous change, which 5/5 splice prediction tools predict no significant impact on normal splicing or ESE binding. A functional study, Quiles_2016, support these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/120394 (1/30120), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Multiple publications have cited the variant in affected individuals, although with limited information (ie, no co-occurrence and cosegregation data). A reputable database cites the variant in 14 individuals with a classification of "likely neutral," with 3 of the individuals carrying another pathogenic BRCA variant, 1 BRCA1, c.3839_3843delinsAGGC (p.Ser1280X) and 2 BRCA2s, c.1310_1313delAAGA (p.Lys437IlefsX22) and c.7234insG (p.Thr2412AspfsX2). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Therefore, taking all availble lines of evidence into consideration, the variant of interest has been classified as "likely benign."
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588977	SCV000888939	benign	not provided	2019-07-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000410590	SCV001140480	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123933	SCV002066465	likely benign	not specified	2019-04-16	criteria provided, single submitter	clinical testing
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000410590	SCV002107491	benign	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001082311	SCV002515228	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000163992	SCV002537819	likely benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149851	SCV003838231	likely benign	Breast and/or ovarian cancer	2022-05-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554711	SCV004761323	likely benign	BRCA1-related disorder	2019-02-21	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000410590	SCV004817579	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV000410590	SCV001243722	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354826	SCV001549536	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 The p.Glu1725= variant was identified in 5 of 1304 proband chromosomes (frequency: 0.004) from Spanish and Algerian individuals or families with (familial or sporadic) breast or ovarian cancers, and was not identified in 385 control chromosomes from healthy individuals (Cherbal 2012 22684231, Uhrhammer 2008 18645608, Infante 2006 16758124, Beristain_2007_17262179). RNA transcript analysis of the variant from cultured lymphocytes showed the variant had no effect on splicing (Quiles_2016_26780556). The variant was also identified in dbSNP (ID: rs191373374) as “With Likely benign allele, Uncertain Significance allele”, the ClinVar database (classified benign, reviewed by an expert panel (2017); submitters: benign by GeneDX and Invitae, and likely benign by ENIGMA, Ambry Genetics and Counsyl) and Clinvitae, but was not in GeneInSight-COGR, COSMIC, MutDB, UMD, BIC, ARUP , LOVD, 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Consortium (Feb 27, 2017) control databases.. The p.Glu1725= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% chance that the variant creates a cryptic 3' acceptor splice site; however, this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588977	SCV001956953	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588977	SCV001964509	likely benign	not provided		no assertion criteria provided	clinical testing