ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3211G>A (p.Glu1071Lys) (rs41293445)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164153 SCV000214769 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000206166 SCV000259400 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1071 of the BRCA1 protein (p.Glu1071Lys). 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) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 184828). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The lysine 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.
GeneDx RCV000255764 SCV000321428 uncertain significance not provided 2018-03-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3211G>A at the cDNA level, p.Glu1071Lys (E1071K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA1 3330G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1071Lys 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 Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1071Lys occurs at a position that is not conserved and is located in the DNA-binding domain (Narod 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 Glu1071Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000164153 SCV000903324 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing

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