ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.316C>T (p.Arg106Cys) (rs587780247)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116153 SCV000186595 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116153 SCV000910727 likely benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Counsyl RCV000411175 SCV000489983 uncertain significance Fanconi anemia, complementation group J 2016-09-06 criteria provided, single submitter clinical testing
Counsyl RCV000409171 SCV000489984 uncertain significance Neoplasm of ovary 2016-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000212298 SCV000150062 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.316C>T at the cDNA level, p.Arg106Cys (R106C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported in individuals with sigmoid, familial prostate, and breast cancer, but was also observed in at least one control (Ray 2009, Pearlman 2016, Easton 2016). BRIP1 Arg106Cys was observed at an allele frequency of 0.02% (7/34,416) in individuals of Latino ancestry 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Arg106Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780051 SCV000917071 likely benign not specified 2017-09-19 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.316C>T (p.Arg106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of gnomAD in 32/287682 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000203 (7/34416). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been reported in affected individuals in the literature, without strong evidence for causality (Ray_2009, Easton_2016, Pearlman_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, based on the relatively high allele frequency of the variant in the control population, this variant is classified as likely benign.
Invitae RCV000205068 SCV000260868 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 106 of the BRIP1 protein (p.Arg106Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587780247, ExAC 0.02%). This variant has been reported in individuals affected with prostate cancer (PMID: 19935797), breast cancer (PMID: 26921362), and colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 128184). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics RCV000411175 SCV000839402 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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