ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3403C>T (p.Gln1135Ter) (rs80357136)

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Total submissions: 10
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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) RCV000077547 SCV000282307 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000236027 SCV000292936 pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.3403C>T at the cDNA level and p.Gln1135Ter (Q1135X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3522C>T. 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 reported in association with hereditary breast and ovarian cancer (Judkins 2005, Caux-Moncoutier 2011, Gutierrez Espeleta 2012, Kanchi 2014, Maxwell 2017). We consider it to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077547 SCV000325650 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574138 SCV000673014 pathogenic Hereditary cancer-predisposing syndrome 2017-12-01 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 RCV000574138 SCV000688435 pathogenic Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000077547 SCV000839895 pathogenic Breast-ovarian cancer, familial 1 2017-05-25 criteria provided, single submitter clinical testing The c.3403C>T (p.Gln1135*) variant in the BRCA1 gene has been reported by multiple clinical laboratories in ClinVar and reviewed by an expert panel as a pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/54868/ ). This variant creates a premature stop codon at amino acid position 1135 of the BRCA1 protein. This variant is thus predicted to result in a loss of function of the protein. The variant was detected in one individual from the ExAC database (http://exac.broadinstitute.org/variant/17-41244145-G-A). This variant thus classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000496327 SCV000918683 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-19 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3403C>T (p.Gln1135X) 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 (e.g., p.Ile1159fsX6 and p.Glu1161fsX3). The variant was absent in 245838 control chromosomes. The c.3403C>T variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. 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.
Sharing Clinical Reports Project (SCRP) RCV000077547 SCV000109348 pathogenic Breast-ovarian cancer, familial 1 2012-01-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077547 SCV000144753 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496327 SCV000587309 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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