ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.800G>A (p.Gly267Glu) (rs80359036)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045386 SCV000073399 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 267 of the BRCA2 protein (p.Gly267Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs80359036, ExAC 0.006%). This variant has been reported in an individual affected with breast cancer, and an individual affected with either breast, ovarian, or pancreatic cancer (PMID: 28288110, 27882536). ClinVar contains an entry for this variant (Variation ID: 52472). 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 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.
Ambry Genetics RCV000164234 SCV000214855 likely benign Hereditary cancer-predisposing syndrome 2017-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
GeneDx RCV000589465 SCV000569059 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.800G>A at the cDNA level, p.Gly267Glu (G267E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 1028G>A. This variant has been observed in at least two breast or ovarian cancer patients (Davies 2017, Alhuqail 2018). BRCA2 Gly267Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly267Glu is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Gly267Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478225 SCV000600776 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589465 SCV000695121 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.800G>A (p.Gly267Glu) variant causes a missense change involving a non-conserved nucleotide with 3/5 in silico tools predict a benign outcome for this variant. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/118818 (1/29708), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. The variant of interest has been observed in HBOC patients via publications. In addition, a PhD dissertation performed multiple functional studies on the variant of interest, which the author indicates that the variant is not sensitive to DNA damage excluding an HR defect, show faster growth than wild type BRCA2 cells but colonies were small and 60% of them show a delayed completion of cytokinesis, to which the author only provides potential hypothesis for this observation and indicates more functional assays need to be performed. In addition, multiple clinical diagnostic laboratories/databases cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies).
Color RCV000164234 SCV000903395 likely benign Hereditary cancer-predisposing syndrome 2016-01-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112833 SCV000145745 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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