ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4478A>G (p.Glu1493Gly) (rs80358679)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218014 SCV000279275 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4478A>G at the cDNA level, p.Glu1493Gly (E1493G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 4706A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu1493Gly was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1493Gly occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Glu1493Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509781 SCV000607938 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000556739 SCV000635370 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1493 of the BRCA2 protein (p.Glu1493Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs80358679, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 126045). 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 glycine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218014 SCV000889048 uncertain significance not provided 2019-07-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763887 SCV000894822 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113308 SCV000146432 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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