ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6469C>G (p.Gln2157Glu) (rs397507859)

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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 RCV000214385 SCV000273246 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000767191 SCV000566530 uncertain significance not provided 2016-04-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6469C>G at the cDNA level, p.Gln2157Glu (Q2157E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 6697C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln2157Glu 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 Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln2157Glu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Gln2157Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000483077 SCV000916914 uncertain significance not specified 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6469C>G (p.Gln2157Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant is absent in 224466 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple clinical diagnostic laboratories classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000462334 SCV000549783 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 2157 of the BRCA2 protein (p.Gln2157Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 229881). 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 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 novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483077 SCV000600704 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing

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