ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3701T>G (p.Phe1234Cys) (rs587778137)

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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 RCV000220406 SCV000272993 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000767212 SCV000279824 uncertain significance not provided 2016-01-22 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3701T>G at the cDNA level, p.Phe1234Cys (F1234C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTT>TGT). BRIP1 Phe1234Cys was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRIP1 Phe1234Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Phe1234Cys occurs at a position that is not conserved and is not located in a known functional domain (Cantor 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Phe1234Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120403 SCV000084555 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000636173 SCV000757605 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 1234 of the BRIP1 protein (p.Phe1234Cys). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and cysteine. 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: 133759). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The cysteine 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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