ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4118_4119AG[1] (p.Glu1373_Ser1374insTer) (rs80357787)

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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) RCV000031151 SCV000300076 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000131891 SCV000186946 pathogenic Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031151 SCV000325856 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000496761 SCV000591493 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Color RCV000131891 SCV000688467 pathogenic Hereditary cancer-predisposing syndrome 2017-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000657802 SCV000779557 pathogenic not provided 2016-12-15 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted BRCA1 c.4120_4121delAG at the cDNA level and p.Ser1374Ter (S1374X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGAG[delAG]TGAA. The deletion creates a nonsense variant, which changes a Serine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.4120_4121delAG, previously reported as 4239delAG, has been observed in multiple individuals with Hereditary Breast and Ovarian Cancer (Montagna 1996, Walsh 2011, Mannan 2016). Based on currently available evidence, we consider this variant to be pathogenic.
3DMed Clinical Laboratory Inc RCV000677798 SCV000803956 pathogenic Neoplasm of the breast 2017-06-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496761 SCV000918799 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4120_4121delAG (p.Ser1374X) 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 was absent in 274930 control chromosomes (gnomAD). The variant, c.4120_4121delAG, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, including one family in which it segregated with disease (Sekine_2001, Montagna_1996). 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. Six 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657802 SCV001133577 pathogenic not provided 2018-09-03 criteria provided, single submitter clinical testing The variant results in a stop gain, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Invitae RCV000496761 SCV001394184 pathogenic Hereditary breast and ovarian cancer syndrome 2019-08-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1374*) 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/or ovarian cancer (PMID: 8968102, 22006311). This variant is also known as 4239delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 37570). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031151 SCV000053751 pathogenic Breast-ovarian cancer, familial 1 2009-04-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031151 SCV000144988 pathogenic Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496761 SCV000587376 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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