ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.427G>T (p.Glu143Ter) (rs80356991)

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Total submissions: 18
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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) RCV000031162 SCV000282326 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048511 SCV000076524 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu143*) 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 observed in many individuals with breast and/or ovarian cancer (PMID: 9333265, 22009639, 24504028, 20104584, 23961350). This variant is also known as 546G>T and E143X in the literature. ClinVar contains an entry for this variant (Variation ID: 37581). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074592 SCV000108677 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.427G>T at the cDNA level and p.Glu143Ter (E143X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also reported as BRCA1 546G>T using alternate nomenclature, this variant has been observed in several individuals and families with breast and/or ovarian cancer and has been reported to be an Irish pathogenic founder variant, estimated to account for approximately 20% of all hereditary breast cancer patients in this population (van Orsuow 1999, Meyer 2003, van der Hout 2006, Janavicius 2010, Solano 2012, Cunningham 2014, Walsh 2015). BRCA1 Glu143Ter is considered pathogenic.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031162 SCV000195884 pathogenic Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162876 SCV000213363 pathogenic Hereditary cancer-predisposing syndrome 2018-07-05 criteria provided, single submitter clinical testing The p.E143* pathogenic mutation (also known as c.427G>T), located in coding exon 5 of the BRCA1 gene, results from a G to T substitution at nucleotide position 427. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This mutation has been reported in several individuals diagnosed with breast and/or ovarian cancer (Perrin-Vidoz L et al. Hum. Mol. Genet. 2002 Nov;11:2805-14; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026). This pathogenic mutation was identified in 2/10030 consecutive patients referred for evaluation by a next-generation cancer panel test (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This alteration has been reported to co-occur with the BRCA2 c.8730delT mutation in a Caucasian patient from Denmark (Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). This alteration has also been reported as a possible Irish founder mutation, after the author noted that it accounted for 22% of all HBOC individuals in an Irish population (Janavičius R. EPMA J. 2010 Sep;1:397-412). It has since been reported in multiple individuals from Western Ireland (McVeigh TP et al. Ir. J. Med. Sci. 2014 Jun;183:199-206). Of note, this alteration is also designated as 546G>T in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074592 SCV000296310 pathogenic not provided 2015-03-16 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031162 SCV000325911 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162876 SCV000537632 pathogenic Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 6 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in many individuals affected with breast and/or ovarian cancer, and is a common cause of hereditary breast cancer in the Irish population (PMID: 23199084, 23884708). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics RCV000465234 SCV000540935 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000074592 SCV000885068 pathogenic not provided 2017-10-19 criteria provided, single submitter clinical testing The BRCA1 c.427G>T, p.Glu143Ter variant (rs80356991) has been reported in patients with breast or ovarian cancer (Shattuck-Eidens 1997, Cunningham 2014), and listed as pathogenic on ClinVar (Variation ID: 37581). The predicted truncated BRCA1 protein lacks homologous recombination activity when expressed in yeast (Caligo 2009). The variant is not been observed in the general population databases, such as the 1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the p.Glu143Ter variant is classified as pathogenic. References: Caligo M et al. (2009) Hum Mutat. A yeast recombination assay to characterize human BRCA1 missense variants of unknown pathological significance. 30(1):123-33. Cunningham J et al (2014). Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 4:4026. Shattuck-Eidens D et al (1997) BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 278(15):1242-50.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048511 SCV000916796 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-31 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.427G>T (p.Glu143X) 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. The variant was absent in 251024 control chromosomes. c.427G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Solano_2013, Judkins_2005, Evans_2003, Nielsen_2016). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Research and Development, ARUP Laboratories RCV001659849 SCV001878820 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031162 SCV000053762 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031162 SCV000145476 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 RCV000048511 SCV000587052 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074592 SCV000591266 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031162 SCV000733673 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000074592 SCV001959757 pathogenic not provided no assertion criteria provided clinical testing

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