ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3664G>T (p.Glu1222Ter) (rs80357356)

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Total submissions: 11
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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) RCV000083196 SCV000299990 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000131817 SCV000186872 pathogenic Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505832 SCV000296427 pathogenic not provided 2016-02-11 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083196 SCV000325717 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496663 SCV000699056 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3664G>T (p.Glu1222X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121334 control chromosomes. Multiple publications have cited the variant in affected individuals, along with multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx RCV000505832 SCV000779361 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3664G>T at the cDNA level and p.Glu1222Ter (E1222X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA1 3783G>T by alternate nomenclature, has been reported in at least one individual with early-onset personal and family history of breast cancer (Churpek 2015), and is considered pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000083196 SCV000839902 pathogenic Breast-ovarian cancer, familial 1 2017-10-30 criteria provided, single submitter clinical testing The c.3664G>T variant is predicted to yield a premature stop codon at amino acid position 1222 of BRCA1 gene, which is one of mechanisms causing BRCA1 defects related breast cancer. This variant is absent in general population (not in gnomad) and observed in multiple breast cancer patients (Breast Cancer Information Core, PMID:25428789). It has been also observed in other clinical labs and reported as a pathogenic. Based on the above evidences, we interpret this variant as pathogenic.
Color RCV000131817 SCV000912035 pathogenic Hereditary cancer-predisposing syndrome 2020-05-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083196 SCV000115270 pathogenic Breast-ovarian cancer, familial 1 2009-08-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083196 SCV000144830 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 RCV000496663 SCV000587330 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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