ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3097G>A (p.Glu1033Lys) (rs273899698)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159975 SCV000210141 uncertain significance not provided 2014-09-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3097G>A at the cDNA level, p.Glu1033Lys (E1033K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, BRCA1 Glu1033Lys has previously been reported as a somatic change in an endometrial tumor according to the Catalogue of Somatic Mutations in Cancer. BRCA1 Glu1033Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1033Lys occurs at a position that is moderately conserved across species and is located in the DNA binding domain (Narod & Foulkes 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Glu1033Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569329 SCV000661075 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000792972 SCV000932303 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1033 of the BRCA1 protein (p.Glu1033Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 182152). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The lysine amino acid residue is 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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