ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2563C>T (p.Arg855Cys) (rs146031731)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215624 SCV000274122 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215624 SCV000689344 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Counsyl RCV000662411 SCV000784842 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2016-12-27 criteria provided, single submitter clinical testing
GeneDx RCV000478148 SCV000568873 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2563C>T at the cDNA level, p.Arg855Cys (R855C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed once in a series of 3,431 unaffected control subjects (Ramus 2015) and in at least one individual with breast cancer (Li 2015). BRIP1 Arg855Cys was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg855Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780055 SCV000917076 uncertain significance not specified 2018-03-28 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2563C>T (p.Arg855Cys) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 283888 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (1.8e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.2563C>T has been reported in the literature in one individual with breast cancer (Tung_2015) and in a breast cancer family who also carried pathogenic BRCA2 BRCA2 c.51_52delAC, p.Arg18Leufs*12 (Li_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Invitae RCV000199690 SCV000255155 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 855 of the BRIP1 protein (p.Arg855Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs146031731, ExAC 0.02%). This variant has been reported in a family with hereditary breast and/or ovarian cancer, however, a pathogenic BRCA2 variant was also identified in this same family (PMID: 26534844). This variant was also reported in an unaffected control individual (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 216789). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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 RCV000709538 SCV000839365 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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