ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2808T>G (p.Asp936Glu) (rs730881485)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590145 SCV000210135 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2808T>G at the cDNA level, p.Asp936Glu (D936E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). Using alternate nomenclature, this variant would be defined as BRCA1 2927T>G. This variant was observed in at least one individual with a personal history of ovarian cancer (Cunningham 2014). BRCA1 Asp936Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA1 Asp936Glu occurs at a position that is not conserved and is located in the DNA binding domain and region of interaction with RAD51 (Chen 1998, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Asp936Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000471242 SCV000549334 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 936 of the BRCA1 protein (p.Asp936Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs730881485, ExAC 0.003%). This variant has been reported in an individual with ovarian cancer (PMID: 24504028). ClinVar contains an entry for this variant (Variation ID: 182149). 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 glutamic acid 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. 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.
Ambry Genetics RCV000566633 SCV000660959 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000590145 SCV000698980 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2808T>G (p.Asp936Glu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/121384 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in the literature in at least one affected individual (Cunningham_2014), without strong evidence for causality. In addition, one clinical diagnostic laboratories and a reputable database classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590145 SCV000888871 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing
Color RCV000566633 SCV000903172 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing

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