ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3768_3769AG[1] (p.Glu1257fs) (rs80357579)

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Total submissions: 19
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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) RCV000031127 SCV000300013 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 RCV000048325 SCV000076338 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 10 of the BRCA1 mRNA (c.3770_3771delAG), causing a frameshift at codon 1257. This creates a premature translational stop signal (p.Glu1257Glyfs*9) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357993, ExAC 0.001%). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 18627636, 23479189, 16683254, 17319787, 23683081). It is also known as 3890_3891delAG and 3889delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 37546). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131814 SCV000186869 pathogenic Hereditary cancer-predisposing syndrome 2018-11-03 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000235232 SCV000292519 pathogenic not provided 2017-08-08 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA1 is denoted c.3770_3771delAG at the cDNA level and p.Glu1257GlyfsX9 (E1257GfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAG[delAG]GAGA. The deletion causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 1257, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.3770_3771delAG, previously reported as 3890_3891delAG, 3888delGA, 3889delAG, and 1257del2, has been observed in association with breast and ovarian cancer (Takahashi 1995, Couch 1996, Liede 2002, Sakamoto 2016) and is a recurrent pathogenic variant within regions of Spain (Esteban Cardeñosa 2010, de Juan Jimenez 2013). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235232 SCV000296287 pathogenic not provided 2015-08-22 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031127 SCV000325752 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031127 SCV000488193 pathogenic Breast-ovarian cancer, familial 1 2016-01-19 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031127 SCV000564304 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Genologica Medica RCV000031127 SCV000577929 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Color RCV000131814 SCV000683133 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031127 SCV000744624 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677799 SCV000803957 pathogenic Ovarian cancer 2017-06-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048325 SCV000918771 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) 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. The variant allele was found at a frequency of 8.1e-06 in 245968 control chromosomes (gnomAD). The variant, c.3770_3771delAG, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Takahashi_1995, Judkins_2005, Hansa_2012, Thirthagiri_2008, Sun_2017). 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. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000031127 SCV000039545 pathogenic Breast-ovarian cancer, familial 1 1999-08-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000031127 SCV000053726 pathogenic Breast-ovarian cancer, familial 1 2012-03-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031127 SCV000144872 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 RCV000048325 SCV000587347 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031127 SCV000733617 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785411 SCV000923983 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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