ClinVar Miner

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

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Total submissions: 7
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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 2020-10-25 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, 22476429). 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 2020-03-23 criteria provided, single submitter clinical testing The p.E1250G variant (also known as c.3749A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3749. The glutamic acid at codon 1250 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in two separate studies of individuals with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier, V et al. Hum Mutat. 2011 Mar;32(3):325-34; Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 2019-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129769 SCV000903264 likely benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194411 SCV001363946 uncertain significance not specified 2019-06-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3749A>G (p.Glu1250Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 246920 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3749A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Zuntini_2018, Lu_2012, Caux-Moncoutier). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four of whom classified the variant as uncertain significance while one reports a classification as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
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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