ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4347A>G (p.Thr1449=) (rs80356840)

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Total submissions: 8
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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) RCV000112321 SCV000578185 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; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV000048531 SCV000076544 benign Hereditary breast and ovarian cancer syndrome 2017-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166538 SCV000217339 likely benign Hereditary cancer-predisposing syndrome 2014-10-21 criteria provided, single submitter clinical testing
GeneDx RCV000437448 SCV000512309 likely benign not specified 2017-10-02 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.
Color RCV000166538 SCV000683172 likely benign Hereditary cancer-predisposing syndrome 2015-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000437448 SCV000699134 benign not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4347A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within East Asian control individuals in the gnomAD database (0.001) is close to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, in certain East Asian subpopulations the variant was observed with an even higher occurrence, e.g. in the Japanese control population it occurred with a frequency of 0.0087 (HGVD), strongly suggesting a benign role for the variant. c.4347A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Han 2006, Judkins 2005, Kim 2006, Lee 2003, Hwang 2017). However, in several of these publications the authors listed the variant of interest as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 benign.
Counsyl RCV000112321 SCV000785875 likely benign Breast-ovarian cancer, familial 1 2017-12-21 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112321 SCV000145064 benign Breast-ovarian cancer, familial 1 2004-12-27 no assertion criteria provided clinical testing

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