ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3749A>G (p.Glu1250Gly) (rs56400215)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044256 SCV000072269 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1250 of the BRCA2 protein (p.Glu1250Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with a personal and/or family history of breast and/or ovarian cancer (PMID: 21120943, 30254663). ClinVar contains an entry for this variant (Variation ID: 51515). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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. 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 RCV000129769 SCV000184578 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000212231 SCV000210323 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3749A>G at the cDNA level, p.Glu1250Gly (E1250G) 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 3977A>G. This variant was observed in two individuals with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011, Lu 2012). BRCA2 Glu1250Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 binding region (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether BRCA2 Glu1250Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212231 SCV000887796 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing
Color RCV000129769 SCV000903264 likely benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113214 SCV000146291 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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