ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5528C>A (p.Ala1843Glu) (rs730881447)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159854 SCV000209898 uncertain significance not provided 2014-10-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5528C>A at the cDNA level, p.Ala1843Glu (A1843E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala1843Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ala1843Glu occurs at a position that is conserved through mammals and is located in the second BRCT domain (Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether BRCA1 Ala1843Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000466347 SCV000549359 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 1843 of the BRCA1 protein (p.Ala1843Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic 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: 182082). 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: "Deleterious"; PolyPhen-2: "Possibly 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.

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