ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.815_824dup (p.Thr276fs) (rs387906563)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129599 SCV000184383 pathogenic Hereditary cancer-predisposing syndrome 2017-10-08 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)
Baylor Genetics RCV000468976 SCV000540938 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Centro de Genética y Biología Molecular,Universidad de San Martín de Porres RCV000019258 SCV000263346 pathogenic Breast-ovarian cancer, familial 1 2015-03-09 no assertion criteria provided research
Color RCV000129599 SCV000683367 pathogenic Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019258 SCV000326435 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000019258 SCV000677715 pathogenic Breast-ovarian cancer, familial 1 2015-03-18 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000019258 SCV000323916 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735513 SCV000863651 pathogenic Breast and/or ovarian cancer 2014-12-18 no assertion criteria provided clinical testing
GeneDx RCV000074602 SCV000108688 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing This duplication of 10 nucleotides in BRCA1 is denoted c.815_824dup10 at the cDNA level and p.Thr276AlafsX14 (T276AfsX14) at the protein level. The surrounding sequence is GTGG[dup10]CACA. The duplication causes a frameshift, which changes a Threonine to an Alanine at codon 276 and creates a premature stop codon at position 14 of the new reading frame. BRCA1 c.815_824dup10 is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as BRCA1 926ins10, 934_943dup10, or 943ins10 using alternate nomenclature, has been reported in association with breast and/or ovarian cancer (Stoppa-Lyonnet 1997, Walsh 2011, Villarreal-Garza 2015). This variant has also been described as a founder pathogenic variant of African origin (Mefford 1999, Pal 2004). Based on currently available evidence, we consider BRCA1 c.815_824dup10 to be pathogenic.
Genologica Medica RCV000019258 SCV000577918 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000019258 SCV000839904 pathogenic Breast-ovarian cancer, familial 1 2017-08-21 criteria provided, single submitter clinical testing The c.815_824 frameshift change in BRCA1 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 9150149, 10417303, 22006311, 15533909]. This variant is classified as pathogenic. It is recommended that the zygosity (heterozygous vs. mosaic) of this change be confirmed by Sanger sequencing as NGS variant calling may lead to skewed allele fractions for an indel of this size.
Integrated Genetics/Laboratory Corporation of America RCV000049156 SCV000699312 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.815_824dupAGCCATGTGG (p.Thr276Alafs) 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.843_846delCTCA/p.Ser282fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121190 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000049156 SCV000077169 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr276Alafs*14) 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 individuals affected with breast and ovarian cancer (PMID: 9150149, 10417303, 28503720, 26681312). This variant is also known as 926ins10, ter289, and 943ins10 in the literature. ClinVar contains an entry for this variant (Variation ID: 55723). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019258 SCV000039546 pathogenic Breast-ovarian cancer, familial 1 1999-08-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074602 SCV000296290 pathogenic not provided 2015-02-10 criteria provided, single submitter clinical testing

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