ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2329T>G (p.Tyr777Asp) (rs397507199)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213379 SCV000273183 likely benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000418137 SCV000518152 likely benign not specified 2015-07-16 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.
Invitae RCV000476108 SCV000549411 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-11-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 777 of the BRCA1 protein (p.Tyr777Asp). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37463). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The aspartic acid amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000213379 SCV000910762 benign Hereditary cancer-predisposing syndrome 2016-11-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000418137 SCV000916778 uncertain significance not specified 2018-07-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2329T>G (p.Tyr777Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 121366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2329T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 likely benign and 1 VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031044 SCV000053638 benign Breast-ovarian cancer, familial 1 2009-06-18 no assertion criteria provided clinical testing

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