ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1255C>T (p.Arg419Trp) (rs150624408)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587794 SCV000150029 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1255C>T at the cDNA level, p.Arg419Trp (R419W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in individuals with prostate, colorectal, breast, or ovarian cancer, but has also been seen in controls (Rutter 2003, Ray 2009, Ramus 2015, Easton 2016, Yurgelun 2017). BRIP1 Arg419Trp was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRIP1 Arg419Trp was observed at an allele frequency of 0.06% (18/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). BRIP1 Arg419Trp 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 Arg419Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116120 SCV000183926 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000206467 SCV000261278 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 419 of the BRIP1 protein (p.Arg419Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs150624408, ExAC 0.06%). This variant has been reported in individuals affected with prostate cancer (PMID: 19935797) and ovarian cancer (PMID: 26315354), as well as in healthy control individuals (PMID: 12872252, 26315354). ClinVar contains an entry for this variant (Variation ID: 128153). 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.
Counsyl RCV000409993 SCV000489933 uncertain significance Fanconi anemia, complementation group J 2016-08-12 criteria provided, single submitter clinical testing
Counsyl RCV000411100 SCV000489934 uncertain significance Neoplasm of ovary 2016-08-12 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415326 SCV000492806 uncertain significance Breast carcinoma 2014-12-05 criteria provided, single submitter clinical testing
Color RCV000116120 SCV000537535 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120413 SCV000600891 uncertain significance not specified 2016-08-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120413 SCV000699660 likely benign not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1255C>T (p.Arg419Trp) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding, DinG/Rad3-type, Helicase-like, DEXD box c2 type, and Helicase superfamily 1/2, ATP-binding domain 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 0.00035 in 302642 control chromosomes in the gnomAD database and publications, including 1 homozygotes. The observed variant frequency is approximately 6-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. c.1255C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer, pancreatic cancer, melanoma, prostate cancer, and colorectal cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (CHEK2 c.1100delC, p.Thr367fsX15). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA RCV000116120 SCV000821953 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000409993 SCV000839384 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587794 SCV000887977 uncertain significance not provided 2019-06-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000206467 SCV000895112 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
ITMI RCV000120413 SCV000084565 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000116120 SCV000787963 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing

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