ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4244A>G (p.Glu1415Gly) (rs1060502399)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478019 SCV000567857 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4244A>G at the cDNA level, p.Glu1415Gly (E1415G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). Using alternate nomenclature, this variant has been previously published as BRCA2 4472A>G. This variant was observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Laitman 2011). BRCA2 Glu1415Gly 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 Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1415Gly occurs at a position that is not conserved and is located in the BRC3 functional domain as well as the RAD51 and POLH binding domains (Cole 2011, 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 Glu1415Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781078 SCV000918888 uncertain significance not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4244A>G (p.Glu1415Gly) 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 8.4e-06 in 238704 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.4e-06 vs 7.50e-04), allowing no conclusion about variant significance. The variant, c.4244A>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Laitman 2011). This report does 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000471686 SCV000549542 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-07-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1415 of the BRCA2 protein (p.Glu1415Gly). 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 an individual affected with breast or ovarian cancer (PMID: 20960228). 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 also 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, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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