ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2542C>T (p.Arg848Cys) (rs45572934)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456342 SCV000547343 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 848 of the BRIP1 protein (p.Arg848Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine 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: 407850). 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 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.
Ambry Genetics RCV000570309 SCV000661599 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-30 criteria provided, single submitter clinical testing The p.R848C variant (also known as c.2542C>T), located in coding exon 17 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2542. The arginine at codon 848 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in 1/5242 controls but not in 13,213 cases from a population-based case control study of breast cancer in the United Kingdom (Easton DF et al. J. Med. Genet., 2016 May;53:298-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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