ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3010G>C (p.Glu1004Gln) (rs786202534)

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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 RCV000165383 SCV000216110 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000206269 SCV000261176 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1004 of the BRCA1 protein (p.Glu1004Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. 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: 185883). 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, 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.
GeneDx RCV000587834 SCV000565795 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3010G>C at the cDNA level, p.Glu1004Gln (E1004Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). Using alternate nomenclature, this variant would be defined as BRCA1 3129G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1004Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Glu1004Gln is located within the RAD51 and DNA binding domains (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Glu1004Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587834 SCV000698996 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3010G>C (p.Glu1004Gln) variant involves the alteration of a conserved nucleotide that does not lie within a known functional domain (InterPro). 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index/p-value). This variant is absent in 121088 control chromosomes (ExAC), but is present in gnomAD (2/276894 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Due to the absence of clinical information and lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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