ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3695_3699GTAAA[1] (p.Val1234fs) (rs80357609)

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Total submissions: 23
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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) RCV000031123 SCV000282314 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 RCV000048287 SCV000076300 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1234Glnfs*8) 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 multiple individuals and families with breast and/or ovarian cancer (PMID: 15024741, 18489799, 24010542, 23479189, 21324516, 25066507). This variant is also known as 3819del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 37542). 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 RCV000131816 SCV000186871 pathogenic Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000235915 SCV000292517 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA1 is denoted c.3700_3704delGTAAA at the cDNA level and p.Val1234GlnfsX8 (V1234QfsX8) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAA[delGTAAA]CAAT. The deletion causes a frameshift, which changes a Valine to a Glutamine at codon 1234, and creates a premature stop codon at position 8 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.3700_3704delGTAAA, also reported as 3695_3699delGTAAA, 3819_3823delGTAAA, and 3819del5 using alternate nomenclature, has been observed in multiple families with Hereditary Breast and Ovarian Cancer syndrome and has been described as a recurrent BRCA1 variant in Eastern European individuals (Foretova 2004, Foretova 2010, Schneegans 2012, de Juan Jimenez 2013, Ratajska 2015). We consider this variant to be pathogenic.
GeneKor MSA RCV000238864 SCV000296798 pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides in exon 11 of BRCA1 mRNA (c.3700_3704delGTAAA), causing a frameshift at codon 1234 and the creation of a premature translation stop signal 8 amino acid residues later p.(Val1234Glnfs*8). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This sequence change has been reported in the international literature in multiple families with Hereditary Breast and Ovarian Cancer syndrome and has been suggested to be a common BRCA1 variant in the Czech Republic (PMID: 15024741 ;22160602 ).This mutation has been described in the mutation database ClinVar (Variation ID: 37542).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031123 SCV000325727 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031123 SCV000488333 pathogenic Breast-ovarian cancer, familial 1 2016-03-03 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031123 SCV000564379 pathogenic Breast-ovarian cancer, familial 1 2015-12-15 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000048287 SCV000586894 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048287 SCV000591463 pathogenic Hereditary breast and ovarian cancer syndrome 2012-12-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235915 SCV000600345 pathogenic not provided 2016-08-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000048287 SCV000605765 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-13 criteria provided, single submitter clinical testing The p.Val1234fs variant in BRCA1 has been reported in >60 individuals with BRCA1 -associated cancers (Brozek 2011, Ratajska 2015, Breast Cancer Information Core (BIC)), and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1234 and leads to a premature termination codon 8 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . Heterozygous loss of function of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-appro ved ENIGMA expert panel (ClinVar SCV000282314.1). In summary, the p.Val1234fs va riant meets criteria to be classified as pathogenic for HBOC in an autosomal dom inant manner.
Color RCV000131816 SCV000683123 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048287 SCV000699059 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The c.3700_3704delGTAAA (p.Val1234Glnfs) variant in BRCA1 gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (~121382 and 246014 chrs tested). The variant of interest has been reported in multiple affected individuals and was shown to segregate with the disease within the family. Multiple reputable databases/clinical laboratories and published reports cited the variant as pathogenic. Taking together, the variant was classified as Pathogenic.
Mendelics RCV000048287 SCV000839249 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000031123 SCV001140547 pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000425 SCV001157235 pathogenic not specified 2019-04-26 criteria provided, single submitter clinical testing The BRCA1 c.3700_3704del; p.Val1234fs variant (rs80357609), also known as 3819del5, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer, and is described as a recurrent BRCA1 variant in Eastern European individuals (Brozek 2011, Foretova 2004, Gorski 2000, Heramb 2018, Konstantopoulou 2014, Machackova 2008, Ratajska 2008, Takahashi 1995). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37542), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Brozek I et al. Prevalence of the most frequent BRCA1 mutations in Polish population. J Appl Genet. 2011 Aug;52(3):325-30. Foretova L et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr;23(4):397-8. Gorski B et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000 Jun;66(6):1963-8. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Konstantopoulou I et al. High prevalence of BRCA1 founder mutations in Greek breast/ovarian families. Clin Genet. 2014 Jan;85(1):36-42. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. Ratajska M et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep. 2008 Jan;19(1):263-8. Takahashi H et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res. 1995 Jul 15;55(14):2998-3002.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235915 SCV001247353 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031123 SCV001429221 pathogenic Breast-ovarian cancer, familial 1 2019-09-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031123 SCV000053721 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031123 SCV000144839 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 RCV000048287 SCV000587333 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785409 SCV000923981 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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