ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.193C>T (p.Gln65Ter) (rs575595017)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568753 SCV000661579 pathogenic Hereditary cancer-predisposing syndrome 2018-01-03 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)
GeneDx RCV000657727 SCV000779477 pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.193C>T at the cDNA level and p.Gln65Ter (Q65X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588194 SCV000699680 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.193C>T (p.Gln65X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 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 (e.g. c.1871C>A, p.Ser624X; c.2255_2256delAA, p.Lys752fsX12; c.2392C>T, p.Arg798X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121242 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000636179 SCV000757611 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2017-08-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln65*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs575595017, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related disease. 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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