ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5636A>G (p.Glu1879Gly) (rs398122536)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571155 SCV000668823 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000571155 SCV000911201 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000219353 SCV000279433 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5636A>G at the cDNA level, p.Glu1879Gly (E1879G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). Using alternate nomenclature, this variant would be defined as BRCA2 5864A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu1879Gly was not observed 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 Glu1879Gly occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). 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 Glu1879Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200011 SCV000254196 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1879 of the BRCA2 protein (p.Glu1879Gly). The glutamic acid residue is moderately 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 observed in a family with breast cancer, but a pathogenic allele was also identified in BRCA2 (Invitae). ClinVar contains an entry for this variant (Variation ID: 91419). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Sharing Clinical Reports Project (SCRP) RCV000076936 SCV000108733 uncertain significance Breast-ovarian cancer, familial 2 2011-03-17 no assertion criteria provided clinical testing

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