ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1600C>T (p.Gln534Ter) (rs142074233)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000238846 SCV000323333 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000236467 SCV000293472 pathogenic not provided 2017-09-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1600C>T at the cDNA level and p.Gln534Ter (Q534X) 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, also published as BRCA1 1719C>T using alternate nomenclature, has been observed in at least three families presenting with breast and/ or ovarian cancer (Machackova 2008). We consider BRCA1 Gln534Ter to be a pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238846 SCV000296406 pathogenic Breast-ovarian cancer, familial 1 2015-11-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000238846 SCV000325103 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781028 SCV000918788 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1600C>T (p.Gln534X) 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. p.Gln541X, p.Gly559fsX13, p.Gln563X). The variant was absent in 245682 control chromosomes. c.1600C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Li_2018, Machackova_2008). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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