ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2119C>T (p.Arg707Cys) (rs764803896)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213828 SCV000279500 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2119C>T at the cDNA level, p.Arg707Cys (R707C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in an individual with Fanconi Anemia-J who also had a second BRIP1 missense variant and weak BRIP1 protein expression on Western blot analysis (Levitus 2005). However, as phase was not described, we cannot be certain that Arg707Cys was in trans with the second missense variant. In vitro functional assays suggests this variant partially impairs helicase activity compared to wild type (Bhari 2018). BRIP1 Arg707Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the helicase domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg707Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227729 SCV000291003 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 707 of the BRIP1 protein (p.Arg707Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs764803896, ExAC 0.009%). This variant has been reported in an individual affected with Fanconi anemia type J (PMID: 16116423). A second BRIP1 missense change, c.1941G>C (p.Trp647Cys), was also identified in that individual but whether these two variants were the cause of disease in that individual remains uncertain. The BRIP gene is also known as FANCJ in the literature. ClinVar contains an entry for this variant (Variation ID: 234570). This variant has been reported to affect BRIP1 protein function (PMID: 29788478). 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 RCV000561689 SCV000661503 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000561689 SCV000909769 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-28 criteria provided, single submitter clinical testing
Mendelics RCV000990001 SCV001140763 likely pathogenic Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV001194768 SCV001364551 pathogenic Fanconi anemia, complementation group J 2011-02-07 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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