ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2457del (p.Asp821fs) (rs80357669)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131356 SCV000186332 pathogenic Hereditary cancer-predisposing syndrome 2018-01-02 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)
Breast Cancer Information Core (BIC) (BRCA1) RCV000031052 SCV000144441 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131356 SCV000683036 pathogenic Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031052 SCV000325361 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031052 SCV000677642 pathogenic Breast-ovarian cancer, familial 1 2015-11-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000047845 SCV000224993 pathogenic not provided 2014-09-04 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031052 SCV000299772 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000047845 SCV000209881 pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.2457delC at the cDNA level and p.Asp821IlefsX25 (D821IfsX25) at the protein level. The normal sequence, with the base that is deleted in brackets, is GTTC[delC]AAAG. This deletion causes a frameshift, which changes an Aspartic Acid to an Isoleucine at codon 821, and creates a premature stop codon at position 25 of the new reading frame. BRCA1 c.2457delC is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously published as BRCA1 2575delC, 2576delC, 819delC, and S819fs, has been reported in multiple individuals with breast and/or ovarian cancer (Couch 1996, Schorge 2001, Pal 2005, Cunningham 2014, Couch 2015). Additionally, in an unusual case of an individual with biallelic BRCA1 variants, this variant was reported in an individual with a likely pathogenic missense variant on the opposite allele who presented with early-onset ovarian cancer as well as multiple congenital abnormalities (Domchek 2013). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000167767 SCV000698956 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2457delC (p.Asp821Ilefs) 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.2515delC, c.2940delA). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121358 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 numerous HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000167767 SCV000075858 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp821Ilefs*25) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357669, ExAC 0.003%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 8807330, 23269703, 24504028, 26718727, 26681312, 24728189). This variant is also known as 2576delC, S819fs, and 819delC in the literature. ClinVar contains an entry for this variant (Variation ID: 37471). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000167767 SCV000605753 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-28 criteria provided, single submitter clinical testing The p.Asp821fs variant in BRCA1 has been reported in >50 individuals with BRCA1- associated cancers (Couch 1996, Bernards 2016, Cunningham 2014, Domchek 2013, Br east Cancer Information Core (BIC), Sharing Clinical Reports Project). This vari ant has been identified in 2/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80357669). This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 821 and leads to a premature termination codon 25 am ino acids downstream. This alteration is then predicted to lead to a truncated o r absent protein. Heterozygous loss of function of the BRCA1 gene is an establis hed disease mechanism in individuals with hereditary breast and ovarian cancer ( HBOC). In addition, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299772.2). In summary, t his variant meets criteria to be classified as pathogenic for HBOC in an autosom al dominant manner.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031052 SCV000195904 pathogenic Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
OMIM RCV000585855 SCV000693736 pathogenic FANCONI ANEMIA, COMPLEMENTATION GROUP S 2013-04-01 no assertion criteria provided literature only
Pathway Genomics RCV000031052 SCV000207338 pathogenic Breast-ovarian cancer, familial 1 2014-11-06 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047845 SCV000296345 pathogenic not provided 2015-05-19 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167767 SCV000587219 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031052 SCV000053646 pathogenic Breast-ovarian cancer, familial 1 2013-03-20 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000031052 SCV000266028 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing

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