ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6255A>T (p.Leu2085Phe) (rs730881579)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160189 SCV000883511 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000160189 SCV000210533 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6255A>T at the cDNA level, p.Leu2085Phe (L2085F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 6483A>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Leu2085Phe was not observed in large population cohorts (Lek 2016). This variant is located in the BRC8 domain (Cole 2011). 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 Leu2085Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000817081 SCV000957621 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2085 of the BRCA2 protein (p.Leu2085Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182271). 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 phenylalanine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160189 SCV000889093 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing

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