ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3401A>T (p.Glu1134Val) (rs762744684)

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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 RCV000220075 SCV000277384 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-22 criteria provided, single submitter clinical testing
Invitae RCV000474129 SCV000549320 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 1134 of the BRCA1 protein (p.Glu1134Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs762744684, ExAC 0.009%). This variant has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 233080). 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: "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 RCV000484803 SCV000564733 uncertain significance not provided 2016-10-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3401A>T at the cDNA level, p.Glu1134Val (E1134V) at the protein level, and results in the change of a Glutamic Acid to a Valine (GAA>GTA). Using alternate nomenclature, this variant would be defined as BRCA1 3520A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1134Val 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 Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1134Val occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Glu1134Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000663155 SCV000786310 uncertain significance Breast-ovarian cancer, familial 1 2018-04-06 criteria provided, single submitter clinical testing

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