ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1372G>T (p.Glu458Ter) (rs587780228)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212309 SCV000885120 pathogenic not provided 2018-03-11 criteria provided, single submitter clinical testing The BRIP1 c.1372G>T; p.Glu458Ter variant (rs587780228), is reported in the literature in individuals with a clinical history of ovarian cancer, breast cancer, glioblastoma, or colon polyps (Norquist 2016, Susswein 2016). This variant is classified as pathogenic by several laboratories in ClinVar (Variation ID: 128156). It is observed in the general population at a low overall allele frequency of 0.006% (2/30950 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Norquist BM et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016 Apr;2(4):482-90. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
Ambry Genetics RCV000116123 SCV000217717 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 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)
Color RCV000116123 SCV000537633 pathogenic Hereditary cancer-predisposing syndrome 2015-08-03 criteria provided, single submitter clinical testing
Counsyl RCV000663293 SCV000786535 pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2018-05-25 criteria provided, single submitter clinical testing
GeneDx RCV000212309 SCV000150032 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1372G>T at the cDNA level and p.Glu458Ter (E458X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in individuals with personal and/or family history of breast and ovarian cancer (Norquist 2015, Susswein 2015, Schoolmeester 2017). We consider BRIP1 Glu458Ter to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781186 SCV000919068 pathogenic Familial cancer of breast 2018-11-08 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1372G>T (p.Glu458X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.5e-05 in 30950 control chromosomes (gnomAD). The variant, c.1372G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Norquist_2016, Schoolmeester_2017, Susswein_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000473135 SCV000547328 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu458*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780228, ExAC 0.002%). This variant has been reported in individuals affected with breast cancer, ovarian cancer, or glioblastoma (PMID: 26681312, 26720728). ClinVar contains an entry for this variant (Variation ID: 128156). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). For these reasons, this variant has been classified as Pathogenic.

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