ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4039_4040AG[1] (p.Gly1348fs) (rs80357727)

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Total submissions: 13
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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) RCV000077560 SCV000300059 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 RCV000074588 SCV000076432 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly1348Asnfs*7) 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 reported in many individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 964913311, 12204006, 23697973, 25418591, 25330149, 27083178). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235130 SCV000108673 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA1 is denoted c.4041_4042delAG at the cDNA level and p.Gly1348AsnfsX7 (G1348NfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAG[delAG]GAAC. The deletion causes a frameshift which changes a Glycine to an Asparagine at codon 1348, and creates a premature stop codon at position 7 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. This variant, also known as BRCA1 4160delAG or 4159delGA by alternate nomenclature, has been associated with hereditary breast and ovarian cancer (Eccles 1998, Troudi 2007, Sugano 2008, Walsh 2011, Gaj 2012, Cybulski 2014, Gonz?lez-Rivera 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000131889 SCV000186944 pathogenic Hereditary cancer-predisposing syndrome 2017-01-25 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 RCV000077560 SCV000266032 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235130 SCV000296350 pathogenic not provided 2015-06-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000235130 SCV000296772 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077560 SCV000325820 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000074588 SCV000588053 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074588 SCV000699101 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4041_4042delAG (p.Gly1348Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is predicted to truncate BCRT domains. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1395X, p.Gln1408X, p.Tyr1563X, etc.). This variant is absent in 121360 control chromosomes from ExAC and has been reported in several HBOC patients/families from literature and clinical databases. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077560 SCV000109362 pathogenic Breast-ovarian cancer, familial 1 2011-11-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077560 SCV000144944 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 RCV000074588 SCV000587369 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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