ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2722G>T (p.Glu908Ter) (rs80356978)

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Total submissions: 26
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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) RCV000077527 SCV000299819 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 RCV000047943 SCV000075956 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu908*) 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 individuals affected with breast and ovarian cancer and glioblastoma (PMID: 8554067, 19949876, 19016756, 25880076). This variant is also known as 2841G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54657). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074576 SCV000108661 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.2722G>T at the cDNA level or p.Glu908Ter (E908X) 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 either through protein truncation or nonsense-mediated mRNA decay. BRCA1 Glu908Ter, previously reported as BRCA1 2841G>T using alternate nomenclature, has been observed in association with familial breast and ovarian cancer (Serova 1996, Sugano 2008, Boukerroucha 2015, Conroy 2017) and is considered pathogenic.
Ambry Genetics RCV000131878 SCV000186933 pathogenic Hereditary cancer-predisposing syndrome 2019-02-16 criteria provided, single submitter clinical testing The p.E908* pathogenic mutation (also known as c.2722G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2722. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in multiple breast and ovarian cancer (HBOC) syndrome kindreds to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Boukerroucha M et al. BMC Cancer. 2015 Mar;15:181; De Brakeleer S et al. Clin. Genet.. 2016 Mar;89:336-40; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). 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 RCV000074576 SCV000296333 pathogenic not provided 2015-04-29 criteria provided, single submitter clinical testing
GeneKor MSA RCV000074576 SCV000296768 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This is a single base substitution, replacing the Glutamate at position 908 of the BRCA1 protein by a Termination codon. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. The mutation database ClinVar contains entries for this variant (Variation ID: 54657).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077527 SCV000325447 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077527 SCV000488226 pathogenic Breast-ovarian cancer, familial 1 2016-01-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047943 SCV000494392 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2722G>T (p.Glu908X) 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. If a stable protein is made, Glu908X is predicted to eliminate the BRCT domain. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Val923fsX76, p.Asp936fsX63, etc.). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121362 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant was cited in multiple HBOC patients in the literature and was shown to co-segregate with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Health, Inc RCV000131878 SCV000537660 pathogenic Hereditary cancer-predisposing syndrome 2020-11-13 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer and glioblastoma (PMID: 19016756, 22006311, 25880076, 26010302, 29470806). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000047943 SCV000605746 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-04 criteria provided, single submitter clinical testing The p.Glu908X variant in BRCA1 has been reported in >60 individuals with BRCA1-a ssociated cancers (Serova 1996, Couch 2015, Boukerroucha 2015, Breast Cancer Inf ormation Core (BIC), Sharing Clinical Reports Project). This variant has been id entified in 1/8600 European chromosomes by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS/; dbSNP rs80356978). This nonsense variant leads to a premature termination codon at position 908, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ov arian cancer (HBOC). In addition, this variant was classified as Pathogenic on S eptember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV0002998 19.2). In summary, this variant meets our criteria to be classified as pathogeni c for HBOC in an autosomal dominant manner.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077527 SCV000743410 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077527 SCV000744648 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000077527 SCV000778595 pathogenic Breast-ovarian cancer, familial 1 2017-10-24 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000763005 SCV000893450 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000077527 SCV001434970 pathogenic Breast-ovarian cancer, familial 1 2019-02-01 criteria provided, single submitter clinical testing The c.2722G>T (p.Glu908*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple individuals affected with breast or ovarian cancer (PMID 8554067, 19016756, 19949876, 22006311, 22009639, 25880076). This variant is not observed in gnomAD database. Therefore, the c.1953_1956delGAAA (p.Lys653Serfs*47) variant in the BRCA1 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000074576 SCV001448152 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001661930 SCV001878980 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) RCV000077527 SCV000109328 pathogenic Breast-ovarian cancer, familial 1 2012-05-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077527 SCV000144522 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148387 SCV000190085 pathogenic Breast neoplasm 2014-06-01 no assertion criteria provided research
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047943 SCV000587250 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074576 SCV000591407 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077527 SCV000733636 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735484 SCV000863621 pathogenic Breast and/or ovarian cancer 2001-10-01 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000074576 SCV001956036 pathogenic not provided no assertion criteria provided clinical testing

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