ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5346G>A (p.Trp1782Ter) (rs80357284)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031239 SCV000300246 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 RCV000131866 SCV000186921 pathogenic Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Michigan Medical Genetics Laboratories,University of Michigan RCV000031239 SCV000267719 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000256177 SCV000321443 pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5346G>A at the cDNA level and p.Trp1782Ter (W1782X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as 5465G>A, has been reported in association with breast and/or ovarian cancer (Sobczak 1997, Geisler 2002, Evans 2003, Perkowska 2003, Kroiss 2005, Machackova 2008, van Harssel 2010, Cybulski 2014) and is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031239 SCV000326287 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031239 SCV000489335 pathogenic Breast-ovarian cancer, familial 1 2016-09-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000496476 SCV000605759 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-27 criteria provided, single submitter clinical testing The p.Trp1782X (c.5346G>A) variant in BRCA1 has been reported in 15 individuals with BRCA1-associated cancers (Breast cancer information core (BIC) database, Ma chackova 2008, Sobczak 1997) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1782, which is predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). Additionally, the p.Trp1782X variant was classified a s Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA Expert Panel (S CV000300246.2). In summary, this variant meets criteria to be classified as path ogenic for HBOC in an autosomal dominant manner based upon its predicted impact to the protein, absence from controls, and multiple reports in affected individu als.
Color RCV000131866 SCV000683301 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256177 SCV000887724 pathogenic not provided 2018-08-11 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV000496476 SCV001361839 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-29 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.5346G>A (p.Trp1782X) 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.5431C>T(p.Gln1811X0), c.5444G>A(p.Trp1815X)). The variant was absent in 277192 control chromosomes (gnomAD). The variant, c.5346G>A has been reported in the literature in multiple individuals affected with ovarian cancer, breast cancer Hereditary Breast and Ovarian Cancer and high risk patients with family history of HBOC (Geisler_2002, Reedy_2002, Kroiss_2005, Pennington_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and supports a loss of function outcome for this variant (Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031239 SCV000053843 pathogenic Breast-ovarian cancer, familial 1 2010-05-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031239 SCV000145472 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031239 SCV000212011 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496476 SCV000587501 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000256177 SCV000778732 pathogenic not provided 2017-01-31 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031239 SCV001238208 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.