ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.213-11T>G (rs80358061)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047725 SCV000075738 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the BRCA1 mRNA. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is present in population databases (rs80358061, ExAC 0.002%). This variant was reported to segregate with disease in a large family affected with breast and ovarian cancer (PMID: 7894493), and has been observed in many unrelated individuals with breast and/or ovarian cancer (PMID: 18284688, 21993507, 25452441, 10923033, 22144684). In the literature, this variant is also known as c.332-11T>G and IVS5-11T>G. ClinVar contains an entry for this variant (Variation ID: 37449). Experimental studies have demonstrated that this variant weakens the consensus acceptor splice site in intron 4, which leads to the use of a cryptic acceptor splice site 59 nucleotides upstream of the 5' end of exon 5 (PMID: 18424508, 23451180). This is expected to result in a frameshift in the BRCA1 mRNA and an absent or truncated protein. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074570 SCV000108655 pathogenic not provided 2017-09-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.213-11T>G or IVS4-11T>G and consists of a T>G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 332-11T>G or BRCA1 IVS5-11T>G using alternate nomenclature. RNA and minigene assays have demonstrated that BRCA1 c.213-11T>G causes aberrant splicing through activation of a cryptic splice acceptor site, introducing a premature stop codon and leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonnet 2008, Colombo 2013). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer, and has been shown to segregate with disease (Friedman 1994, Musolino 2005, John 2007, Colombo 2013, Song 2014, Wong-Brown 2015). We consider this variant to be pathogenic.
Ambry Genetics RCV000131898 SCV000186953 pathogenic Hereditary cancer-predisposing syndrome 2014-09-25 criteria provided, single submitter clinical testing
Counsyl RCV000031030 SCV000220836 pathogenic Breast-ovarian cancer, familial 1 2014-10-24 criteria provided, single submitter literature only
Color RCV000131898 SCV000292144 pathogenic Hereditary cancer-predisposing syndrome 2015-02-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074570 SCV000296273 pathogenic not provided 2015-02-04 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031030 SCV000325254 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000469831 SCV000540930 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506173 SCV000602679 pathogenic not specified 2016-09-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047725 SCV000698919 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-15 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.213-11T>G variant affects a conserved intronic nucleotide. 3/5 splice-site tools predict the variant to create a new cryptic splice site and/or weaken the cononical splice site. This in silico predicted result is proven by multiple functional studies showing that this variant leads to a splicing defect, resulting in an extra 59 base pairs at the end of intron 4 and introducing a premature stop codon. This variant was found in 1/121156 control chromosomes at a frequency of 0.0000083, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). However, the variant has been found in multiple HBOC patients or individuals undergoing BRCA1/2 testing as reported in literature and clinical databases. Additionally, several clinical labs and clinical databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000047725 SCV000966958 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-20 criteria provided, single submitter clinical testing The c.213-11T>G variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and has segregated with disease in multiple affected relati ves (Friedman 1994, John 2007, Smith 2012, Wong-Brown 2015, BIC database). This variant has also been reported by multiple clinical laboratories in ClinVar (Var iation ID# 37449). Additionally, this variant has been identified in 3/111540 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org). Sequencing of patient RNA has shown that this variant leads to a retention of 59 base pairs at the 3' end of intron 5, which is predicted to r esult in a premature stop codon (Friedman 1994, Colombo 2013). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individual s with hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the frequency in patients and segregation studies. ACMG/AMP cr iteria applied: PS4, PP1_Strong.
Sharing Clinical Reports Project (SCRP) RCV000031030 SCV000053624 pathogenic Breast-ovarian cancer, familial 1 2013-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031030 SCV000144670 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 RCV000047725 SCV000587038 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735531 SCV000863669 pathogenic Breast and/or ovarian cancer 2007-01-26 no assertion criteria provided clinical testing

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