ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5252G>A (p.Arg1751Gln) (rs80357442)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162992 SCV000213480 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112579 SCV000145412 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000168520 SCV000219261 likely benign not specified 2017-02-06 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148392 SCV000190091 uncertain significance Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research
Color RCV000162992 SCV000683277 likely benign Hereditary cancer-predisposing syndrome 2016-01-08 criteria provided, single submitter clinical testing
Counsyl RCV000112579 SCV000488772 benign Breast-ovarian cancer, familial 1 2016-06-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168520 SCV000591600 uncertain significance not specified 2012-11-19 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112579 SCV000244393 benign 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 1 based on posterior probability = 0.000206
GeneDx RCV000168520 SCV000209988 likely benign not specified 2017-08-15 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.
Integrated Genetics/Laboratory Corporation of America RCV000168520 SCV000699228 likely benign not specified 2018-03-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5252G>A (p.Arg1751Gln) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/5 splice prediction tools in Alamut predict that this variant does not affect normal splicing, which was confirmed by an allelic-imbalance assay (Caux-Moncoutier_2009). The variant allele was found at a frequency of 4.1e-05 in 246270 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.1e-05 vs 1.00e-03), allowing no conclusion about variant significance. c.5252G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality (Stoppa-Lyonnet_1997, Gad_2002, deJuan_2009). In one large association study, the variant was found to be not associated with risk of breast cancer in the Caucasian population (Shimelis_2017). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8346G>A, p.Trp2788X), providing supporting evidence for a benign role. In addition, multiple functional assays suggest the variant of interest to have comparable transcriptional, growth and localization activities as well as homologous recombination in yeast compared to wild-type, though it was also suggested to cause a mild destabilization of the protein (Lee_2010, Rowling_2010, Williams_2003, and Thouvenot_2016, Lodovichi_2016). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000257892 SCV000076896 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000168520 SCV000605910 likely benign not specified 2017-05-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759558 SCV000888944 likely benign not provided 2017-05-19 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000168520 SCV000587483 benign not specified 2014-01-31 no assertion criteria provided research

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