ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2934T>G (p.Tyr978Ter) (rs80357115)

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Total submissions: 13
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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) RCV000031074 SCV000299858 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000195361 SCV000076030 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr978*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant is a known common cause of breast and ovarian cancer in non-Ashkenazi Jewish individuals (PMID: 9667663, 17591843, 11493753, 22399190), although it has been observed in individuals from other ethnicities (PMID: 15951957). This variant is also known as 3053T>G and Tyr1017ter in the literature. ClinVar contains an entry for this variant (Variation ID: 37493). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000048017 SCV000210140 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2934T>G at the cDNA level and p.Tyr978Ter (Y978X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>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 familial breast/ovarian cancer and is considered to be a common pathogenic variant in individuals of Jewish (non-Ashkenazi) ancestry in Iraq and other middle Eastern countries (Theodor 1998, Shiri-Sverdlov 2001, Quintana-Murci 2005, Hall 2009; Laitman 2012). We therefore consider this variant to be pathogenic.
Ambry Genetics RCV000162860 SCV000213347 pathogenic Hereditary cancer-predisposing syndrome 2018-01-17 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048017 SCV000296282 pathogenic not provided 2019-04-04 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031074 SCV000325501 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195361 SCV000591416 pathogenic Hereditary breast and ovarian cancer syndrome 2013-06-24 criteria provided, single submitter clinical testing
Color RCV000162860 SCV000683074 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Counsyl RCV000031074 SCV000785813 pathogenic Breast-ovarian cancer, familial 1 2017-12-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195361 SCV000916718 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2934T>G (p.Tyr978X) 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.Pro981fsX19 and p.Asn1002fsX22). The variant was absent in 246118 control chromosomes. The c.2934T>G variant has been reported in the literature in numerous 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. Seven 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031074 SCV000053670 pathogenic Breast-ovarian cancer, familial 1 2012-08-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031074 SCV000144586 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 RCV000195361 SCV000587263 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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