ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3475G>A (p.Ala1159Thr) (rs368610199)

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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 RCV000222116 SCV000274370 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000521348 SCV000618487 uncertain significance not provided 2017-05-18 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3475G>A at the cDNA level, p.Ala1159Thr (A1159T) 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 pathogenic or benign. BRIP1 Ala1159Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ala1159Thr occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Ala1159Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000222116 SCV000903943 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing
Invitae RCV000808973 SCV000949107 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-10-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1159 of the BRIP1 protein (p.Ala1159Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. 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: 230724). 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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