ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1357G>A (p.Ala453Thr) (rs587780227)

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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 RCV000221894 SCV000274413 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000221894 SCV000903102 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000116122 SCV000150031 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1357G>A at the cDNA level, p.Ala453Thr (A453T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a pediatric glioneuronal tumor (Johnson 2017). BRIP1 Ala453Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRIP1 Ala453Thr 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 BRIP1 Ala453Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524937 SCV000633553 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 453 of the BRIP1 protein (p.Ala453Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587780227, ExAC 0.003%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128155). 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 threonine 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.

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