ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3058A>G (p.Thr1020Ala) (rs1064793073)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569465 SCV000668940 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000482641 SCV000564818 uncertain significance not provided 2015-02-24 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3058A>G at the cDNA level, p.Thr1020Ala (T1020A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Thr1020Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Thr1020Ala occurs at a position that is moderately conserved across mammals and is located in the region of interaction with BRCA1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRIP1 Thr1020Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000706762 SCV000835831 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1020 of the BRIP1 protein (p.Thr1020Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 418099). 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 alanine 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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