ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1941G>C (p.Trp647Cys) (rs786202760)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000582028 SCV000689297 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
GeneDx RCV000481541 SCV000567795 uncertain significance not provided 2015-09-01 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1941G>C at the cDNA level, p.Trp647Cys (W647C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGC). This variant has been reported with another missense variant in an individual with Fanconi Anemia, however, phase is not reported (Levitus 2005). BRIP1 Trp647Cys 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 Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Trp647Cys occurs at a position that is conserved across species and is located in the helicase domain (Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Trp647Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000226066 SCV000290997 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-06-02 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 647 of the BRIP1 protein (p.Trp647Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This sequence change was reported in an individual affected with Fanconi anemia type J. A second BRIP1 missense change, c.2119C>T (p.Arg707Cys), was also identified in this individual. Whether this variant segregates with disease remains uncertain (PMID: 16116423). ClinVar contains an entry for this variant (Variation ID: 241635). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.
Mendelics RCV000709542 SCV000839372 likely pathogenic Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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