ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.900A>C (p.Glu300Asp) (rs80356861)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049182 SCV000077195 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 300 of the BRCA1 protein (p.Glu300Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid 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: 55747). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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.
GeneDx RCV000236740 SCV000293329 uncertain significance not provided 2015-11-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.900A>C at the cDNA level, p.Glu300Asp (E300D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). Using alternate nomenclature, this variant would be defined as BRCA1 1019A>C. This variant has been reported to possibly affect protein function based on conservation and ancestral sequence analysis (Fleming 2003, Pavlicek 2004). BRCA1 Glu300Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA1 Glu300Asp occurs at a position that is conserved in mammals and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Glu300Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000771560 SCV000904137 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111506 SCV000143948 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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