ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9161C>T (p.Pro3054Leu) (rs80359172)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766655 SCV000210497 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9161C>T at the cDNA level, p.Pro3054Leu (P3054L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). BRCA2 c.9161C>T, previously reported as c.9389C>T, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro3054Leu was not observed in large population cohorts (Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Pro3054Leu is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Pro3054Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160165 SCV000600847 uncertain significance not specified 2017-04-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573424 SCV000665981 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
Invitae RCV000690429 SCV000818113 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 3054 of the BRCA2 protein (p.Pro3054Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182259). 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 leucine 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.
Color RCV000573424 SCV000906699 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing

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