ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1898T>C (p.Ile633Thr) (rs587780232)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000116132 SCV000150041 uncertain significance not provided 2013-11-08 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1898T>C at the cDNA level, p.Ile633Thr (I633T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC) in exon 13. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. BRIP1 Ile633Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution of a neutral non-polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. This gene, which is involved in DNA damage repair as part of the Fanconi Anemia pathway, has been recently described in association with cancer risk, but the small number of patients studied precludes specific cancer risk assessment. Based on the currently available information, we consider BRIP1 Ile633Thr to be a variant of unknown significance. The variant is found in HEREDICANCER panel(s).
Invitae RCV000546290 SCV000633580 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2017-06-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 633 of the BRIP1 protein (p.Ile633Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine 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 a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128164). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on BRIP1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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