ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2411_2412del (p.Gln804fs) (rs80357664)

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Total submissions: 14
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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) RCV000031047 SCV000282279 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000047829 SCV000075842 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln804Leufs*5) 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: 10667595, 16168118, 18489799, 26681312, 25777348). This variant is also known as 2530delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 37466). An experimental study has shown that lymphocytes of individuals who carry this variant generate higher numbers of micronuclei after radiation exposure and are deficient in repair of radiation-induced DNA damage (PMID: 10667595). 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 RCV000131426 SCV000186407 pathogenic Hereditary cancer-predisposing syndrome 2018-01-23 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)
GeneDx RCV000159906 SCV000210023 pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in BRCA1 is denoted c.2411_2412delAG at the cDNA level and p.Gln804LeufsX5 (Q804LfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGTC[delAG]TGTG. The deletion causes a frameshift, which changes a Glutamine to a Leucine at codon 804, and creates a premature stop codon at position 5 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.2411_2412delAG, also published as 2411delAG and 2530delAG, has been reported in several women with a history of breast and/or ovarian cancer (Rothfuss 2000, Pal 2005, Pohlreich 2005, Chisholm 2008, Machackova 2008, Spearman 2008, Couch 2015, Meisel 2017). We consider this variant to be pathogenic.
GeneKor MSA RCV000159906 SCV000296767 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 RCV000031047 SCV000325348 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000458659 SCV000540951 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159906 SCV000600287 pathogenic not provided 2016-09-03 criteria provided, single submitter clinical testing
Color RCV000131426 SCV000683033 pathogenic Hereditary cancer-predisposing syndrome 2015-02-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047829 SCV000698948 pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2411_2412delAG (p.Gln804LeufsX5) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250542 control chromosomes (gnomAD). c.2411_2412delAG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Couch_2015, Pal_2005, Pohlreich_2003, Weber_2006, Susswein_2016). 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. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) and one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000159906 SCV000806914 pathogenic not provided 2017-09-12 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031047 SCV000053641 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031047 SCV000144421 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 RCV000047829 SCV000587213 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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