ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1969C>T (p.Gln657Ter) (rs397508926)

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Total submissions: 4
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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) RCV000256717 SCV000323383 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000256717 SCV000325205 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000657568 SCV000779305 pathogenic not provided 2014-10-24 criteria provided, single submitter clinical testing This mutation is noted BRCA1 c.1969C>T at the cDNA level and p.Gln657Ter (Q657X) 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. This variant has been reported in association with hereditary breast cancer and is considered pathogenic (Peixoto 2006).
Integrated Genetics/Laboratory Corporation of America RCV000779889 SCV000916777 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1969C>T (p.Gln657X) 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.2001dupA, p.Leu668fsX5; c.2019delA, p.Glu673fsX28; c.2035A>T, p.Lys679X). The variant was absent in 276820 control chromosomes (gnomAD). The variant, c.1969C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Peixoto_2014, Peixoto_2006, Judkins_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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