ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1240C>T (p.Gln414Ter) (rs368796923)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129878 SCV000184695 pathogenic Hereditary cancer-predisposing syndrome 2017-08-04 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 RCV000129878 SCV000689256 pathogenic Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing
Counsyl RCV000409609 SCV000489993 likely pathogenic Fanconi anemia, complementation group J 2016-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000411128 SCV000489994 likely pathogenic Neoplasm of ovary 2016-09-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000701846 SCV000893464 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000445256 SCV000515873 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1240C>T at the cDNA level and p.Gln414Ter (Q414X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 at least one individual undergoing multi-gene panel testing in a clinical laboratory (LaDuca 2017) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781179 SCV000919060 likely pathogenic Familial cancer of breast 2018-08-03 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1240C>T (p.Gln414X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1871C>A (p.Ser624X), c.2255_2256delAA (p.Lys752fsX12), c.2392C>T (p.Arg798X)). The variant allele was found at a frequency of 4.1e-06 in 245868 control chromosomes (gnomAD). The variant, c.1240C>T, has been reported in the literature with limited information (Hu_2018, La Duca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000701846 SCV000830666 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln414*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs368796923, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 141382). 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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