ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.751C>T (p.Arg251Cys) (rs752309409)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165345 SCV000216069 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000165345 SCV000903617 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Counsyl RCV000662796 SCV000785613 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-10-10 criteria provided, single submitter clinical testing
GeneDx RCV000219928 SCV000279333 likely pathogenic not provided 2017-07-06 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.751C>T at the cDNA level, p.Arg251Cys (R251C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was shown to be functionally deficient in several in vitro assays, including a complementation assay of a BRIP1 null cell line and a DNA binding assay (Guo 2014). Additionally, this variant was found in trans with a BRIP1 missense variant, His396Asp, in an individual with Fanconi Anemia (Chandrasekharappa 2013). BRIP1 Arg251Cys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Arg251Cys occurs at a position that is conserved across species and is located in the Helicase Domain IA (Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRIP1 Arg251Cys to be a likely pathogenic variant.
Invitae RCV000206065 SCV000260454 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 251 of the BRIP1 protein (p.Arg251Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs752309409, ExAC 0.001%). This variant has been reported in an individual affected with Fanconi anemia (PMID: 23613520). In that individual, this variant was found in trans with a second BRIP1 variant of uncertain significance, c.1186C>G (p.His396Asp). Also, the variant has been observed in an individual affected with breast cancer (PMID: 26556299). ClinVar contains an entry for this variant (Variation ID: 185848). The Arg251Cys missense change occurs in the BRIP1 helicase motif Ia. Experimental studies have shown that this missense change severely disrupts the helicase activity of the BRIP1 protein, rendering it unable to contribute to DNA repair (PMID: 24573678, 27107905). 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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