ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.788-751G>T (rs28897686)

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Total submissions: 21
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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) RCV000019241 SCV000300004 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 RCV000048311 SCV000076324 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1250*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs28897686, ExAC 0.003%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 7894491, 12497638, 24504028, 24728189). This variant is also known as 3867G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 17672). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074586 SCV000108671 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.3748G>T at the cDNA level and p.Glu1250Ter (E1250X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3867G>T. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 Glu1250Ter has been reported in association with breast and ovarian cancer (Castilla 1994, Ahmad 2012, Cunningham 2014, Weren 2016) and is considered pathogenic.
Ambry Genetics RCV000131811 SCV000186866 pathogenic Hereditary cancer-predisposing syndrome 2018-01-22 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)
University of Washington Department of Laboratory Medicine,University of Washington RCV000019241 SCV000266030 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074586 SCV000296296 pathogenic not provided 2015-02-16 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019241 SCV000325737 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000465125 SCV000540952 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000048311 SCV000588048 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048311 SCV000591470 pathogenic Hereditary breast and ovarian cancer syndrome 2012-11-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506391 SCV000602708 pathogenic not specified 2017-01-11 criteria provided, single submitter clinical testing
Counsyl RCV000019241 SCV000677650 pathogenic Breast-ovarian cancer, familial 1 2015-06-17 criteria provided, single submitter clinical testing
Color RCV000131811 SCV000683129 pathogenic Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048311 SCV000699068 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-23 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3748G>T (p.Glu1250X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3904G>T/p.Glu1302X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121388 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple affected individuals and functional study showed variant with ~10% of relative HDR activity in comparison to WT BRCA1 (Lu_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000019241 SCV000743401 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000019241 SCV000744626 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
OMIM RCV000019241 SCV000039529 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019241 SCV000109357 pathogenic Breast-ovarian cancer, familial 1 2012-04-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019241 SCV000144858 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 RCV000048311 SCV000587340 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000019241 SCV000733619 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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