ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.595G>C (p.Ala199Pro) (rs376582345)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566628 SCV000661415 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000758913 SCV000279959 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.595G>C at the cDNA level, p.Ala199Pro (A199P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 823G>C. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Ala199Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Ala199Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467809 SCV000549675 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 199 of the BRCA2 protein (p.Ala199Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 234884). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758913 SCV000887857 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing

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