ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5333A>G (p.Asp1778Gly) (rs80357041)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000589573 SCV000076958 likely benign not provided 2019-02-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129616 SCV000184409 benign Hereditary cancer-predisposing syndrome 2014-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000048945 SCV000209990 likely benign not specified 2017-09-15 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048945 SCV000591616 likely benign not specified 2014-08-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589573 SCV000600418 likely benign not provided 2019-06-20 criteria provided, single submitter clinical testing
Color RCV000129616 SCV000683298 likely benign Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589573 SCV000699243 likely benign not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5333A>G (p.Asp1778Gly) variant located in the BRCT domain on the surface of the structure and distant from the phosphopeptide binding site (UniProt, Gaboriau_2015) involves the alteration of a conserved nucleotide at the start of exon 21 and is predicted to be damaging by 3/4 in silico (SNPs&GO not captured due to low reliability index). Due to its location, the variant is predicted to have a role in splicing; however 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of an ESE site. Multiple functional studies (in vitro minigene as well as mRNA analysis) show that it has no effect in splicing (Thomassen_2011, Colombo_2013, Ahlborn_2015). In addition, the variant has no effect on homology-directed recombination (HDR), protein folding, phosphopeptide binding and transcription (Lee_2010, Lu_2015). This variant was found in 1/120994 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple HBOC patients/families or in individuals undergoing BRCA1/2 testing. In one reported family, while this variant was found in the proband, it was not found in the affected mother, suggesting a possible lack of cosegregation evidence against pathogenicity (Colombo_2013). In ClinVar, while three labs classify it as benign/likely benign, two labs classify it as uncertain significance. Taken together, this variant is currently classified as Likely Benign.
Counsyl RCV000077617 SCV000785002 likely benign Breast-ovarian cancer, familial 1 2017-03-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077617 SCV000109420 benign Breast-ovarian cancer, familial 1 2010-07-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077617 SCV000145467 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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