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
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
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
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
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
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.
GeneKor MSA RCV000116120 SCV000821953 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000120413 SCV000084565 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000587794 SCV000699660 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1255C>T (p.Arg419Trp) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the helicase ATP-binding domain (UniProt) and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC and controls from publications (Ramus_JNCI_2015; Rutter_HM_2003) in 50/128128 control chromosomes at a frequency of 0.0003902, which is approximately 6 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. However, one large case-control study (Ramus_JNCI_2015) detected the variant in five epithelial ovarian cancer patients (5/6472 chromosomes) compared to one control (1/6862 chromosomes) in heterozygous state, for an odds ratio of 5.31, suggesting that it is possibly associated with elevated risk of ovarian cancer. However, co-segregation and co-occurrence data were not provided, thereby limiting a thorough analysis. Whether or not this variant is a risk variant for ovarian cancer needs to be further confirmed by other case-control studies. In another large case-control study, this variant was not associated with increased risk for breast cancer (Haiman_PLOS Genetics_2013). This variant was also found in two affected brothers from a prostate cancer family (Ray_BJC_2009); no other family members were available for genotyping for cosegregation analysis. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as a variant of uncertain significance. Taking all the data together, and considering the relatively high frequency in the general population and a lack of co-segregation and co-occurrence data in the literature, this variant is classified as VUS-possibly benign.
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.
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 RCV000120413 SCV000600891 uncertain significance not specified 2016-08-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587794 SCV000887977 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000116120 SCV000787963 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing

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