ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2392C>T (p.Arg798Ter) (rs137852986)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212324 SCV000150048 pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRIP1 c.2392C>T at the cDNA level and p.Arg798Ter (R798X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRIP1 Arg798Ter, also published as c.2533C>T using alternate nomenclature, has been reported in multiple individuals with Fanconi anemia, many of whom were homozygous for this variant (Levitus 2005, Levran 2005, DiNardo 2016, Ghazwani 2016). This variant has also been observed in association with breast, ovarian, and prostate cancer (Seal 2006, Kote-Jarai 2009, McInerney 2010, Pennington 2014, Ramus 2015, Lhota 2016, Thompson 2016, Tung 2016, Frey 2017). A large case/control analysis by Easton et al. (2016) suggested that BRIP1 Arg798Ter was not associated with a substantial increase in overall breast cancer risk, but did show weak evidence of an increased risk for ER-negative and triple negative breast cancer subtypes. Based on currently available evidence, we consider BRIP1 Arg798Ter to be pathogenic.
Ambry Genetics RCV000116139 SCV000186705 pathogenic Hereditary cancer-predisposing syndrome 2018-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000205436 SCV000262207 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 798 (p.Arg798*) of the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported to segregate with disease in families affected with Fanconi anemia (PMID: 16116423, 16116424). It has also been seen in individuals affected with ovarian cancer (PMID: 24240112) and suspected Lynch syndrome (PMID: 25980754), as well as in individuals and families with breast cancer (PMID: 17033622, 19763819, 26822949) and prostate cancer (PMID: 19127258, 24556621). This variant is also known as 2533C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 4738). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). Pathogenic variants in BRIP1 have been associated with an approximate 2-fold increased risk for breast cancer (PMID: 17033622). One study suggested that individuals with the p.Arg798* variant did not have significantly increased risk for breast cancer, although when the analysis was restricted to ER-negative and triple-negative breast cancers, an increased risk could not be discounted (PMID: 26921362). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000116139 SCV000266058 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000116139 SCV000292128 pathogenic Hereditary cancer-predisposing syndrome 2015-02-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000394625 SCV000404594 uncertain significance Neoplasm of the breast 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000312325 SCV000404595 pathogenic Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing The c.2393C>T (p.Arg798Ter) variant is a stop-gained variant, described in three studies in which it is found in 18 Fanconi anemia patients, including 11 in a homozygous state, three in a compound heterozygous state, and in five alleles of unspecified zygosity (Levitus et al. 2005; Levran et al. 2005; Ghazwani et al. 2016). The p.Arg798Ter variant was absent from 50 controls but is reported at a frequency of 0.00024 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Arg798Ter variant is classified as pathogenic for Fanconi anemia.
Counsyl RCV000005004 SCV000489935 likely pathogenic Fanconi anemia, complementation group J 2016-08-18 criteria provided, single submitter clinical testing
Counsyl RCV000409918 SCV000489936 likely pathogenic Neoplasm of ovary 2016-08-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000504276 SCV000593778 pathogenic Breast cancer, early-onset 2017-03-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212324 SCV000600905 pathogenic not provided 2017-03-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515368 SCV000611254 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000005004 SCV000699691 pathogenic Fanconi anemia, complementation group J 2016-01-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212324 SCV000807133 pathogenic not provided 2015-10-30 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116139 SCV000821717 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000005004 SCV000839368 pathogenic Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778127 SCV000914252 pathogenic BRIP1-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The BRIP1 c.2392C>T (p.Arg798Ter) variant, also known as c.2533C>T, is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg798Ter variant has been reported in at least seven studies in which it is found in a total of 27 individuals, including in a homozygous state in 12 individuals with Fanconi anemia (FA), in a compound heterozygous state in five individuals with FA, and in a heterozygous state in six individuals with prostate cancer, in two with ovarian cancer, and in one with endometrioid cancer, and in unknown zygosity in one individual with FA (Levran et al. 2005; Levitus et al. 2005; Kote-Jarai et al. 2009; Leongamornlert et al. 2014; Pennington et al. 2014; Ramus et al. 2015; Ghazwani et al. 2016). The variant is noted to segregate with disease in four families with FA (Levran et al. 2005; Levitus et al. 2005). The p.Arg798Ter variant was identified in a heterozygous state in one of 4090 control alleles and is reported at a frequency of 0.000280 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg798Ter variant is classified as pathogenic for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000005004 SCV000025180 pathogenic Fanconi anemia, complementation group J 2005-09-01 no assertion criteria provided literature only

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