ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5175A>G (p.Glu1725=) (rs191373374)

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Total submissions: 11
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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 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;
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: 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 and ovarian cancer syndrome 2020-11-24 criteria provided, single submitter clinical testing
Counsyl RCV000410590 SCV000488591 likely benign Breast-ovarian cancer, familial 1 2016-05-03 criteria provided, single submitter clinical testing
Color Health, Inc 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 1 2019-05-28 criteria provided, single submitter clinical testing
Brotman Baty Institute,University of Washington RCV000410590 SCV001243722 not provided Breast-ovarian cancer, familial 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.

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