ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.139C>G (p.Pro47Ala) (rs28903098)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116124 SCV000186330 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000116124 SCV000902624 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
Counsyl RCV000409748 SCV000489947 uncertain significance Fanconi anemia, complementation group J 2016-08-18 criteria provided, single submitter clinical testing
Counsyl RCV000410864 SCV000489948 uncertain significance Neoplasm of ovary 2016-08-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000199377 SCV000895119 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000587908 SCV000150033 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.139C>G at the cDNA level, p.Pro47Ala (P47A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). In vitro functional assays have shown BRIP1 Pro47Ala to abolish ATPase activity and result in weak helicase activity and a less stable protein product than wild type (Cantor 2001, Cantor 2004, Gupta 2006, Gupta 2007, Wu 2008). This variant has been observed in several individuals with either a personal or family history of breast or ovarian cancer and at least one individual with suspected Lynch syndrome; however, it has also been reported in control subjects and individuals with pathogenic variants in other genes explaining their phenotype (Cantor 2001, Seal 2006, Kanchi 2014, Yurgelun 2015, Pinto 2016, Pearlman 2017). In addition, internal data are not highly suggestive of pathogenicity, including the frequency of observations at this laboratory, as well as the lack of a reported history of ovarian cancer in many internal cases. BRIP1 Pro47Ala was observed at an allele frequency of 0.02% (69/277,164), with one homozygous observation, in large population cohorts (Lek 2016). This variant is located in Helicase Domain I (Cantor 2001). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Due to the conflicting information, we consider BRIP1 Pro47Ala to be a variant of uncertain significance.
GeneKor MSA RCV000116124 SCV000821954 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000005002 SCV000593776 uncertain significance Breast cancer, early-onset 2018-01-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778130 SCV000914255 uncertain significance BRIP1-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The BRIP1 c.139C>G (p.Pro47Ala) variant has been reported in two studies in which it is found in a heterozygous state in a total of five patients, all with a family history of breast cancer (Cantor et al. 2001; Seal et al. 2006). Only the BRIP1 gene was screened in both studies. The p.Pro47Ala variant was also detected in a heterozygous state in four of 2081 controls who were 46 years of age at the time of study (Seal et al. 2006). Based on age of the individuals, disease status cannot be fully determined in the control cohort. Additionally, the p.Pro47Ala variant is reported at a frequency of 0.00038 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cultured cells demonstrated that the p.Pro47Ala variant protein has a reduced half-life compared to wild type protein and also exhibits complete loss of ATPase and helicase activity (Cantor et al. 2001; Cantor et al. 2004). The evidence for this variant is limited. The p.Pro47Ala variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000587908 SCV000699663 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.139C>G (p.Pro47Ala) variant is located in the Helicase, ATP-binding domain (via InterPro) causes a missense change involving a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a "damaging" outcome. Multiple functional assays have been performed to assess the effect of this variant on BRIP1 properties, which indicate that the variant inactivates ATPase and helicase functions, however, the implications of these observations have yet to be firmly established in the role of tumorigenesis. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 31/123398 (1 homozygote, 1/4184), which does exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000 for HBOC. The variant of interest has been reported in multiple affected individuals via publications in isolation, along with affected individuals having a co-occurrence with another potentially pathogenic variant such as BRCA1, c.5266dup (p.Gln1756ProfsX74 - classified as pathogenic by LCA), PALB2, c.1240C>T (p.Arg414X - not yet scored), and BRCA2, c.8327T>G (p.L2776X - not yet classified), along with the variant being implicated as being lost in a tumor. An assocation study, Seal_2006 did not find an association for BrC risk for this variant. In addition, multiple clinical diagnostic laboratories/databases/publications cite the variant with conflicting classifications: "uncertain significance" or "deleterious/pathogenic." Therefore, due to the conflicting evidence obtained for this variant, the variant of interest has been classified as a "Variant of Uncertain Significance," until additional information such as cosegregation studies and/or more established information as to the implication of the observed functional study findings role in tumorigenesis.
Invitae RCV000199377 SCV000255146 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-06-24 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 47 of the BRIP1 protein (p.Pro47Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs28903098, ExAC 0.04%), including one homozygous individual. This variant has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 11301010, 17033622, 24448499, 21964575, 26921362), as well as in unaffected control individuals (PMID: 17033622, 24448499, 21964575, 26921362). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 4736). Experimental studies have shown that this missense change results in the loss of BRIP1 ATPase and helicase activities in vitro (PMID: 14983014, 17145708). Additional experimental studies have also shown this change results in reduction of BRIP1 protein, reduction of homologous recombination, and increases the frequency of long-tract gene conversion compared to wild-type (PMID: 28911102). 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 RCV000409748 SCV000839405 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000005002 SCV000025178 pathogenic Breast cancer, early-onset 2019-04-19 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200979 SCV000600892 uncertain significance not specified 2017-04-29 criteria provided, single submitter clinical testing

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