ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5109T>G (p.Tyr1703Ter) (rs80356974)

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Total submissions: 14
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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) RCV000077597 SCV000300202 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 RCV000195365 SCV000076810 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1703*) 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 has been reported in individuals affected with breast and/or ovarian cancer (PMID: 11748305, 12491499, 19941162). This variant is also known as 5228T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 55403). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000048797 SCV000210199 pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5109T>G at the cDNA level and p.Tyr1703Ter (Y1703X) at the protein level. The substitution creates a nonsense variant, changing a Tyrosine to a premature stop codon (TAT>TAG). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as 5228T>G using alternate nomenclature, has been reported in individuals for whom clinical testing for Hereditary Breast and Ovarian Cancer syndrome was pursued (Eng 2001, Euhus 2002, Adem 2003, Schroeder 2010, Tutt 2010) and is considered pathogenic.
Ambry Genetics RCV000162883 SCV000213370 pathogenic Hereditary cancer-predisposing syndrome 2017-04-27 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)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077597 SCV000296430 pathogenic Breast-ovarian cancer, familial 1 2016-03-04 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077597 SCV000326157 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077597 SCV000489268 pathogenic Breast-ovarian cancer, familial 1 2016-09-16 criteria provided, single submitter clinical testing
Color RCV000162883 SCV000688537 pathogenic Hereditary cancer-predisposing syndrome 2017-01-12 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000077597 SCV000839888 pathogenic Breast-ovarian cancer, familial 1 2017-03-10 criteria provided, single submitter clinical testing The c.5109T>G (p.Tyr1703*) variant has been reported in 18 patients in the Breast Cancer Information Core database. This variant was also reported in multiple patients in ClinVar and classified as a pathogenic variant by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/55403/) This variant creates a premature stop codon at amino acid position 1703 of the BRCA1 protein and is thus predicted to result in a loss of function of the protein. The variant has not been detected in the ExAC database. This variant thus classified as pathogenic and actionable.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048797 SCV000887713 pathogenic not provided 2016-03-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195365 SCV000916776 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5109T>G (p.Tyr1703X) 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.5126delG, p.Gly1709fsX5; c.5177_5180delGAAA, p.Arg1726fsX3; c.5239C>T, p.Gln1747X). The variant was absent in 246168 control chromosomes (gnomAD). The variant, c.5109T>G, has been reported in the literature and databases in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Tutt_2010,Adem_2002, Schroeder_2015, Eng_2001). 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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic."Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077597 SCV000109400 pathogenic Breast-ovarian cancer, familial 1 2012-07-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077597 SCV000145316 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 RCV000195365 SCV000587465 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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